Delta Opioid Receptor Modulators as Non-Addictive Medications
John Traynor1
1Edward F. Domino Research Center and Departments of Pharmacology and Medicinal Chemistry,
University of Michigan, Ann Arbor, 48109, USA
Chronic pain and depression comprise two of the most common medical ailments experienced worldwide and often present as co-morbid. The delta-opioid receptor (DOR) and its endogenous ligands have been implicated in mood regulation and chronic pain. Because of this, DOR is considered a viable target for the management of depression and certain pain states, including migraine headaches. The potential use of DOR agonists is supported by preclinical data and the fact that, unlike mu-opioid receptor (MOR) agonists, they are not self-administered nor do they cause respiratory depression. However, many DOR agonists cause convulsions in preclinical rodent and non-human primate models, and DOR agonists have failed to progress through clinical trials due to lack of efficacy at non-convulsive doses.
Allosteric modulators acting at a non-orthosteric site on DOR, such as the prototypical xanthenedione BMS-986187, enhance DOR signaling and provide a DOR agonist-sparing effect. Consequently, we show that BMS-986187 enhances the beneficial antidepressant-like and antinociceptive actions of exogenous DOR agonists and, in some cases, can be effective by enhancing endogenous opioid peptide activity. On the other hand, BMS-986187 does not show convulsive activity alone nor does it enhance the proconvulsive action of DOR agonists. Unfortunately, BMS-986187 is not a druggable molecule and exhibits activity both in vitro and in vivo at MOR and kappa opioid receptors (KOR) that limit its usefulness, leading to potential abuse liability and dysphoria, respectively.
In a structure-activity study, we identified several BMS-986187 derivatives that retain high allosteric potency at DOR without allosteric activity at MOR or KOR, including pyridyl derivatives that are approximately 150-fold selective for DOR over MOR or KOR as determined by in vitro functional biochemical assays. These compounds selectively enhance DOR agonism in vivo in measures of antihyperalgesia and antinociception, while remaining silent at MOR or KOR. Recent published work suggests the binding site for the xanthenedione modulators is similar across the opioid receptors. Further experiments suggest the compounds may bind to MOR and KOR but lack allosteric efficacy.
Overall, the findings identify selective pharmacological tools for investigating DOR allosteric modulation as a therapeutic strategy for the management of pain conditions and depressive disorders.
Acknowledgements: Supported by NIDA grants R37 DA039997 and R42 DA056254.
Engineering Intranasal Kappa Opioid Receptor Antagonist Nanotherapeutics to Prevent Pain-Induced Negative Affect and Opioid Escalation
Jose Moron-Concepcion1
1Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110
Although opioid analgesics remain effective for pain management, their long-term use is associated with serious adverse consequences, including hyperalgesia, tolerance, opioid misuse, and opioid use disorder (OUD), limiting their utility in chronic pain treatment. Endogenous opioid peptides acting at mu, kappa, and delta opioid receptors regulate not only nociception but also reward, aversion, and affective states. Consequently, these systems represent attractive therapeutic targets with the potential to provide analgesia while minimizing the liabilities of conventional opioid therapies. However, the clinical translation of peptide-based therapeutics has been hindered by poor metabolic stability and limited blood-brain barrier penetration. Chronic pain is increasingly recognized as a disorder of both sensory and affective processing. Disruption of mesocorticolimbic circuits contributes to the anhedonia, motivational deficits, and mood disturbances commonly observed in chronic pain patients and may increase vulnerability to opioid misuse.
Dr. Jose Morón-Concepción will present preclinical studies identifying the dynorphin/KOR system as a critical mediator of pain-induced negative affect and opioid vulnerability. These studies demonstrate that maladaptive KOR signaling within mesolimbic circuits contributes to motivational impairments and facilitates escalation of opioid intake in the setting of persistent pain. The presentation will further describe the development of innovative brain-targeted therapeutic approaches, including intranasal formulations and nanoliposome-based delivery systems loaded with KOR antagonists. These strategies are designed to achieve spatially selective modulation of KOR signaling through direct nose-to-brain delivery, enabling microdosing, minimizing systemic exposure and unwanted adverse effects, and restoring affective and motivational function in chronic pain states. Collectively, this work establishes a translational framework for developing next-generation, non-addictive therapeutics that simultaneously target chronic pain, negative affect, and opioid misuse risk.
Agonists or Antagonists, That is the Question
Yan Zhang1
1Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298
Fentanyl overdose is still a major impact to our community. Current fentanyl counteracting agents suffer from patient compliance due to withdrawal symptoms. Development of fentanyl overdose specific counteracting agents is, therefore, still imperative. We decided to adopt the fentanyl structural skeleton to develop novel mu opioid receptor antagonists. Through construction of a small molecule library and systematic structure activity relationship studies of these novel chemical entities, we have identified a series of potent mu opioid receptor antagonists that are capable to effectively reverse fentanyl induced respiratory depression in a mouse model. Further drug development efforts are warranted to define them as drug candidates to treat fentanyl overdose.
The Journey from Idea to IND: A Tale of Drug Development at Two ‘First-in-class’ Molecular Targets for SUD
Nurulain T. Zaveri1
1Astraea Therapeutics, Mountain View, CA 94043
Substance use disorders and ‘dependence’ to substances is recognized as a chronic RELAPSING brain disease characterized by alterations in brain regions from persistent use that has yielded several potential pharmacological targets for intervention. However, there have been no new chemical entities or new treatment mechanisms to treat SUDs, not even at the time the Opioid crisis was unfolding. Interestingly, the last new medication approved by the FDA for SUD, with a ‘new mechanism’ was Pfizer’s varenicline (ChantixTM) two decades ago in 2006. At Astraea, we took the path of working on first-in-class pharmacological targets for addiction mechanisms, distinct from previous failed approaches, supported by newer advances in addiction mechanisms. Using a small-molecule ligand-driven approach for new target validation, and medicinal chemistry/lead optimization, Astraea Therapeutics advanced two pipeline programs at two SUD-related pharmacological targets, from validation of target biology, through to IND development of oral, small-molecule drug candidates, to IND approval, and onward into clinical development. In my brief talk, I will share some insights gained on this journey through drug discovery and preclinical-to-clinical development in this challenging area of CNS drug development.
Nucleus Accumbens Representation of Heroin and Methamphetamine Self-Administration
Matthew C. Broomer1, Caroline E. Clark1, Kalia N. Halim1, Nicholas J. Beacher2, Giovanni Barbera1, & Da-Ting Lin1
1National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224
2Department of Psychology, Wittenberg University, Springfield, OH 45501
Concurrent abuse of opioids and psychostimulants represents a significant public health concern. Preclinical models of substance use disorder often focus on a single class of drug, despite evidence that opioids and psychostimulants utilize different mechanisms of action. Electrophysiological data suggests that neural activity within canonical reward circuitry differentially represents opioid- vs. psychostimulant-seeking behavior, but these data lack cell-type specificity and longitudinal tracking of individual neurons over the entire course of self-administration. Thus, a within-subjects comparison of the neural bases of opioid vs. psychostimulant self-administration will clarify the extent to which these behaviors are driven by distinct and/or overlapping ensembles.
We used miniscopes to record activity from D1- and D2-expressing NAc neurons in vivo and applied machine learning-assisted analyses to characterize behavioral changes throughout concurrent self-administration of heroin and methamphetamine. Rats were trained to perform two distinct operant responses, one to self-administer heroin and the other to self-administer methamphetamine, on alternating days for twenty days, then underwent a drug preference test followed by ten days of forced abstinence and a second preference test.
Combined analysis of neural imaging data and three-dimensional pose tracking data revealed distinct subpopulations of NAc MSNs associated with either heroin lever approach or meth lever approach. The activity of these neurons appeared to correspond to the seeking of a particular drug type: heroin lever approach neurons were not active during methamphetamine lever approach and were similarly active when rats approached the heroin lever during methamphetamine sessions, when the heroin lever was unavailable (and vice-versa). These distinct patterns of neural activation were underscored by qualitative behavioral differences in heroin vs. methamphetamine self-administration. When responding for heroin, rats emitted more “redundant responses,” i.e., responses during the infusion period that had no programed consequences. This higher rate of heroin seeking was mirrored by a general preference for heroin over methamphetamine during both choice tests. In the second choice test, however, we found mixed evidence for incubation of heroin craving, whereas rats consistently demonstrated incubation of methamphetamine craving.
These data reveal subtle neurobehavioral differences between heroin and methamphetamine self-administration and highlight the need for further preclinical research on polysubstance abuse.
Acknowledgements: NIDA IRP Histology and Imaging Core
Endogenous Neuronal Signaling Complexes and Psychedelic Drug Actions
Nicholas J. Wright1, Yi-ting Chiu1, Blake Fordyce1, Dewran Kocak1, Pierre Llorach1, Jessica Walsh1 and Bryan L. Roth1
1UNC School of Medicine
In this talk I will summarize recent findings where we have successfully isolated, purified and determined the high-resolution structures of endogenous GPCR complexes which are essential for the actions of psychedelic drugs.
Structural Pharmacology of Psychedelics – Beyond the 5-HT2A Receptor
Daniel Wacker
Icahn School of Medicine at Mount Sinai
Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin receptor 5-HT2A. However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-MeO-DMT, a psychedelic found in the toxin of Colorado River toads. Although 5-HT1A is a validated therapeutic target, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. We map the molecular underpinnings of 5-MeO-DMT pharmacology through cryo-EM structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signaling potency, efficacy and selectivity. Moreover, we show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.
The Role of N343 in Activation and Functional Selectivity of 5-HT2A Receptors
Charles Nichols1
1Health Sciences Center, Louisiana State University
Psychedelics acting at 5-HT2A receptors have recently shown in clinical trials to be effective therapeutics for several neuropsychiatric conditions including depression, anxiety, and substance use disorders. Certain psychedelics are also potent anti-inflammatory agents across multiple models of inflammatory diseases including cardiovascular disease, asthma, and rheumatoid arthritis. Interestingly, neither Gαq/calcium nor β-arrestin recruitment appear to be correlated with anti-inflammatory activity. Structure activity relationship analysis indicates that engagement of N343 may be critical for anti-inflammatory activity. For this analysis we used a series of novel phenethylamine and tryptamine ligands designed to probe interactions with N343 in in vitro studies employing both wild type and mutant N343A receptors, molecular dynamics simulations, and behavioral experiments in mice and rats. Surprisingly, molecules predicted to more directly engage N343 by extending an oxygen towards it on a molecular tether from the main scaffold demonstrated reduced behavioral activity in the head twitch response despite being full efficacy agonists at calcium mobilization. Further, some of our novel molecules produced long lasting antidepressant-like effects equivalent to psilocybin in WKY rats. Together, our data indicate that engagement of N343 is important for anti-inflammatory activity, and that specific engagement produces a concurrent reduction in HTR, enabling us to develop non-HTR-inducing full efficacy receptor agonists with therapeutic potential for psychiatric disorders like depression and SUD.
Preclinical Studies Examining the Prohedonic Effects of Psychedelics
Brian D. Kangas1
1McLean Hospital, Harvard Medical School, Belmont, MA 02478
Anhedonia, the loss of pleasure or lack of reactivity to previously rewarding stimuli, is a core symptom of several psychiatric disorders, including major depression. Despite its transdiagnostic manifestations and relevance to overall patient wellbeing, there are no approved pharmacological treatments specifically for anhedonia. While conventional antidepressant medications such as selective serotonin reuptake inhibitors have broad utility in many psychiatric disorders, they often fail to reduce anhedonia and may even exacerbate it, leading to a generalized blunting of emotional responses following continued treatment. Interestingly, modern treatment approaches, including both ketamine and psilocybin, show promise in ameliorating anhedonia and may do so independently of reductions in other depressive symptoms. This talk will present an overview of studies examining the prohedonic effects of psychedelics, ketamine, and key positive/negative control drugs using the Probabilistic Reward Task (PRT). The PRT was developed to objectively quantify reward responsiveness as a surrogate for anhedonic phenotypes in clinical populations and was subsequently reverse-translated for laboratory animals. Overall, results indicate psychedelic treatment in the rodent PRT produced desirable prohedonic effects on task performance that rival ketamine, notwithstanding interesting differences in time course of action. Studies with 5-HT2A antagonists and non-psychedelic 5-HT2A agonists suggest observed prohedonic efficacy depends, at least in part, on the 5-HT2A receptor.
Structure-Based Design of Selective Bitopic Agonists for the Dopamine D3 Receptor
Alessandro Bonifazi1
1Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, TX 77555
The dopamine D2 and D3 receptors (D2R and D3R) control motor functions, cognition, motivation and emotional behaviors. Dysregulation in dopaminergic signaling is associated with several CNS disorders marked by impulsive decision-making. There is a long-standing challenge in the pharmacological distinction between D2R and D3R and their agonist-bound active states. We build on our discovery of a new selectivity site on the D3R (H291.32-E902.65-G94ECL1) to design subtype selective agonists binding towards the first transmembrane helix. This allowed us to discover a ligand-induced ordering of TM1 unique to D3R, yielding a selectivity site for drug development. We identified new first-in-class partial (AB12-82 and AB13-73A) and full agonists (AB13-08 and AB13-46A) with D3R sub-nanomolar affinity, picomolar potencies and subtype selectivity >2,800-100,000 fold. Off-target screening and in vitro pharmacokinetic data support the translational potential towards future in vivo studies for these unique tools, dissecting the (patho)physiological role of D3R in neurological and neuropsychiatric processes.
The Role of Synaptic Zn²⁺ in Dopaminergic Signaling and Cocaine-Induced Neuroadaptations
Oscar Solis1, Ingrid Schoenborn1, William Dunne1, Anna Tischer1, Michael Michaelides1
1Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224
Synaptic Zn²⁺ is co-released with glutamate from a subset of glutamatergic neurons and acts as an endogenous modulator of dopamine neurotransmission. Previous studies have shown that Zn²⁺ binds to the dopamine transporter (DAT) and enhances cocaine-induced behaviors. However, its role in other components of the dopaminergic system and in cocaine-induced neuroadaptations remains incompletely understood. Altered Zn²⁺ homeostasis has been implicated in several central nervous system disorders, including substance use disorders, highlighting the importance of understanding how synaptic Zn²⁺ regulates neural circuit function.
In this study, we combine receptor autoradiography, fiber photometry, and chemogenetic approaches to investigate the role of synaptic Zn²⁺ during repeated cocaine exposure. Findings demonstrate that Zn²⁺ modulates DAT and dopamine receptor binding and reveal dynamic changes in synaptic Zn²⁺ signaling, dopamine release, dopaminergic terminal activity, and D2 neuron signaling in the nucleus accumbens during cocaine sensitization. In addition, chemogenetic manipulation of cortical Zn²⁺-releasing neurons provides insight into the contribution of these circuits to cocaine-induced behavioral and neural adaptations.
Together, these findings support a role for synaptic Zn²⁺ in regulating dopaminergic transmission and cocaine-induced neuroadaptations, providing new insight into the interaction between glutamatergic Zn²⁺ signaling and dopamine circuits involved in substance use disorders.
Targeting the Serotonin System with an AI-Derived Polypharmacy Strategy for Fentanyl Use Disorder
Valeria Lallai1, Samuel Kho2, Alexa C. Martin2, James P. Fowler1, Madison L. Roach1,4, Kevin Wang1, Kendyl N. Laumann1, Tyler G. Morrison4, Mina Palaniappan1, Malia Bautista1, Allison S. Mogul1, Jinjutha E. Cheepluesak1, Bijay Shrestha2, Dhanaji M. Lade2, Julia Lagomarsino1, Vaishnavi Narayan2, Jayson Uffens2, Waldemar Lernhardt2, Saman Mirzaei2, Ian Jenkins2, Arturo R. Zavala4, Jonathan R.T. Lakey2,3, Robert Tinder2, and Christie D. Fowler1
1Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA USA
2GATC Health, Irvine, CA USA
3Department of Surgery, University of California Irvine, Irvine, CA, USA
4Department of Psychology, California State University Long Beach, Long Beach, CA, USA
The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, including fentanyl. Here, we developed a therapeutic drug based on a newly developed artificial intelligence (AI)-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. Two top candidate compounds, GATC-021 and GATC-1021, were synthesized and validated with in vitro screening for target specificity. Thereafter, the drug candidates were examined for their effectiveness in modulating opioid reinforcement and intake in a preclinical rodent model. We found that GATC-1021, which targets the 5-HT2A and 5-HT6 receptors, was highly selective in attenuating fentanyl self-administration in male and female rats, with retained effectiveness following repeated dosing. Following GATC-1021 treatment, an increase in the percentage of thin dendritic spines in the hippocampus was evidenced, and GATC-1021 was further found to modulate gene expression patterns in addiction-relevant brain regions following fentanyl-induced alterations. These findings validate GATC’s AI-based platform with its polypharmacy-focused drug development approach and further support the clinical potential of GATC-1021 as a promising therapeutic for those suffering from opioid use disorder.
Acknowledgements: These studies were funded by a sponsored research project from GATC Health to CDF. VL, JPF, ASM, KNL, and CDF were also supported by NIH grants to CDF (U01 DA053826, R01 DA051831 and R01 DA058493). JL, MB and MP were supported by Tobacco-Related Disease Research Program grants to CDF (T32IR4866) and VL (T34IP8023).
Psilocybin Reduces Opioid Seeking Behavior and Modulates Both mRNA and Cytokine Expression in the Prefrontal Cortex in a Pre-Clinical Model of Fentanyl Self-Administration
Amy Stringer1,2, Wickensonn Norze1,2, Sean Hayduk1,2, Scott M Rawls1,2 and Stephanie Daws1,2
1Department of Neural Sciences, 2Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University 3500 N Broad St, Philadelphia, PA 19140
Opioid use disorder (OUD) leads to thousands of overdose deaths annually. FDA-approved treatments for OUD are methadone, buprenorphine and naltrexone. While these medications reduce mortality and provide symptomatic relief, they are associated with risk of overdose, precipitated withdrawal, and inadequate suppression of craving. Individuals living with OUD need alternative prospects to pharmacologically treat and support their recovery. Clinical studies have demonstrated psilocybin has therapeutic potential for treatment of substance use disorders, with a low abuse potential and safe therapeutic profile. Data published from our lab support these findings; we have demonstrated that an acute administration of psilocybin following opioid abstinence, but prior to relapse testing, reduces heroin seeking behavior in a rodent opioid self-administration (SA) model. Due to the rise of human use of synthetic opioid agonists, we evolved our rodent opioid SA model from heroin to fentanyl SA. We hypothesized that an acutely administered dose of psilocybin that reduced heroin seeking behavior would be efficacious for reducing fentanyl craving behavior. We tested this by administering psilocybin following three weeks of forced abstinence from fentanyl SA, prior to a cue-induced relapse test. Rats in the psilocybin treatment group responded significantly less on the cue-paired lever during relapse testing compared to vehicle-treated rats. Additionally, we report psilocybin may accelerate extinction of opioid seeking and reduce seeking behavior following a fentanyl re-exposure event during abstinence. Bulk RNA sequencing from the prefrontal cortex (PFC) and cytokine analysis from both the nucleus accumbens and PFC of rats that underwent fentanyl SA with psilocybin treatment was performed to begin to identify mechanisms through which psilocybin may reduce fentanyl seeking behaviors. We report significant biological pathways of genes regulated in the PFC following psilocybin and fentanyl and highlight key gene and cytokine expression signatures that may be evaluated in future studies to understand the molecular consequences of psilocybin use in the context of reduction of opioid seeking behaviors.
Acknowledgements: NIDA, Department of Neural Sciences, Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University
Effects of “Bifunctional” Mu Opioid Peptide, Nociceptin/Orphanin FQ Peptide (NOP) Receptor Agonists in Nonhuman Primate Models of Substance Use Disorders
Paul W Czoty1, Joshua N. Prete1, Emily A Cronin1, Marissa B. Costa1, Gerta Cami-Kobeci2, Stephen M. Husbands2
1Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA 27157
2Department of Life Sciences, University of Bath, Claverton Down, Bath, UK BA2 7AY
Since their discovery 30 years ago, receptors for the nociceptin/orphanin FQ peptide (NOP) have generated great interest as targets for novel pharmacotherapies. An initial interest in such drugs as non-addictive analgesics soon expanded to psychiatric disorders including substance use disorders. Consistent with data from rodent models, our laboratory has generated data in nonhuman primates (NHP) to support drugs that function as partial agonists at both mu opioid peptide and NOP receptors, called “bifunctional agonists,” as promising pharmacotherapies for cocaine use disorder (CUD), alcohol use disorder (AUD) and cocaine-alcohol polysubstance use (PSU).
In our NHP model of CUD and PSU, 12 rhesus monkeys self-administer cocaine one hour per day, five days per week. At least 90 minutes after the session, six monkeys drink a sweetened 4% ethanol solution (2.0 g/kg) over one hour. The other six drink a non-alcoholic solution. The bifunctional agonist BU08028 had equivocal effects on cocaine self-administration across monkeys when given acutely. When administered chronically, however, BU08028 decreased the reinforcing effects of a low dose of self-administered cocaine in three of four subjects. We also examined whether bifunctional agonists would reinstate extinguished cocaine self-administration. Responding was reinstated by cocaine in all subjects and by buprenorphine (itself a bifunctional agonist) in half of the subjects, but by neither BU08028 nor its analog BU12005.
In our highly translational NHP model of AUD, monkeys have access to ethanol and water 22 hours/day, 5 days/week. Food-maintained responding is monitored and animals are observed for indications of adverse effects. In this model, acute treatment with bifunctional agonists and chronic treatment with BU08028 decreased ethanol drinking over weeks in the absence of adverse effects or development of tolerance. Additional studies with this model have used PET imaging to track changes in NOP receptors over the course of ethanol drinking.
Taken together, these results implicate NOP receptors as important modulators of the abuse-related effects of cocaine and alcohol and provide encouraging data to support NOP receptor agonists as novel pharmacotherapies. Moreover, they illustrate the important contributions of NHP models of substance use disorders in the translational pipeline from rodent models to the clinic.
Acknowledgements: Funding for these studies provided by NIH grants R01 DA062224, R01 AA027566, T32 AA007565.
Biased Modulation of NTSR1 on Alcohol and Feeding Behavior
Zoe McElligott1
1Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
Dr. Zoe McElligott will present data demonstrating that systemic, biased modulation of neurotensin R1 receptors (NTSR1) with SBI-553 alters the consumption of alcohol and alcohol-related behaviors and physiology, and motivated feeding behavior. Neurotensin in the lateral, but not the medial CeA enhances GABAergic transmission, which is in turn blocked by SBI-553. In the BNST, neurotensin similarly potentiates GABA signaling but in a sex dependent manner that is only partially blocked by SBI-553. We hypothesize that NTSR1 signaling in the BNST may be through additional downstream effectors in male mice. Examining feeding relevant circuits, we find that SBI-553 differentially alters the activation of these brain regions in a sex and feeding state dependent manner. We believe these data lay the foundation for targeting NTSR1 via biased modulation as a potential pharmacotherapeutic for both alcohol use disorder and eating disorders.
Preclinical Evidence of Nr4a1 as a Novel Therapeutic Target in Cocaine Use Disorder
Elizabeth A Heller1,2, Kyle Czarnecki1, Soumita Ghosh2, Aleksa Milosavljevic3, Dirk Trauner1,3
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, 19104
2Rafias LLC, Philadelphia, Pennsylvania, 191473
3Department of Chemistry, School of Arts & Sciences, University of Pennsylvania 19104
National rates of cocaine use are rising, with approximately 2.4 million persons reporting cocaine use disorder in 2019 1–3. However, no medications have been approved for cocaine use disorder. Using fundamental approaches, we recently validated Nr4a1 as a novel target to suppress cocaine reward behavior in mice 4,5. Nr4a1/Nurr77 is an orphan nuclear receptor that plays an integral role in neuronal homeostasis and neuroprotection in response to hyperexcitation 6–8. The small molecule, Cytosporone B (CsnB), is a naturally occurring Nr4a1 agonist with strong affinity for Nr4a1 (EC50 = 0.278 nM) and its ligand-binding domain (EC50 = 0.115 nM) 9. We recently established that (1) cocaine increases Nr4a1 in mouse striatum and (2) Nr4a1 activation by CRISPRa or systemic administration CsnB suppresses mouse cocaine reward behavior 4,5.
We are now engaged in synthesis and screening of CsnB derivatives that activate human/mouse NR4A1/Nr4a1 and characterization of lead compound(s) using direct binding assays, synthetic feasibility, and pharmacokinetics. We have completed the initial drug discovery and development (DDD) milestones of target identification (TI), and target validation (TV) through prior publication 4 and development of an Nr4a1 Target Dossier and defined a Target Product Profile (TPP) to assess the technical and commercial feasibility of the project for cocaine use disorder patients. We quantify biological activity of each analog as (1) increased transactivation of NR4A1/Nr4a1 mRNA and protein expression in human (HEK293T) and mouse (N2a) cell lines and (2) Nr4a1 response element (NurRE) luciferase reporter activation. In addition, lead compounds (LCs) are evaluated for effects on expression of downstream transcriptional targets of NR4A1/Nr4a1 implicated in dopamine homeostasis and reward pathophysiology. These data will be compared to calculated KD values to identify compounds with the highest affinity binding sites that are the most active with respect to target gene regulation. Finally, we assay lead analogs for direct binding to recombinant NR4A1 C-terminal/ligand binding domain using both surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Compounds which directly bind NR4A1 will be further characterized based on pharmacokinetics (absorption, distribution, metabolism, and excretion (ADME)), and selected for IND-enabling studies.
Our overall goal is to identify a commercially viable, NR4A1-activator lead compound that has the optimal attributes for preclinical testing and IND application initiation. These results are expected to have a positive impact because there is currently no approved medication for cocaine use disorder and tens of thousands of overdose deaths each year. Importantly, NR4A1 is a first-in-class therapeutic target in cocaine use disorder, harnessing the power of gene regulatory mechanisms to reverse the deleterious effects of chronic cocaine exposure.
The Efficacy of GLP-1 Agonists in Treating Substance Use Disorder in Patients
Joji Suzuki1
1Division of Addiction Treatment and Prevention, Mass General Brigham, AMC Psychiatry Department
Brigham and Women’s Hospital, Boston, MA
GLP-1 receptor agonists, originally developed for diabetes and obesity, act on brain reward circuits and are emerging as a novel pharmacotherapy for substance use disorders. This talk reviews the pharmacology of GLP-1 receptor agonists, briefly reviews the neurobiology underlying how addiction treatment is conceptualized, followed by the clinical evidence to date, including two positive randomized controlled trials of semaglutide for alcohol use disorder. Safety considerations, including disordered eating risk, drug-drug interactions, and psychiatric tolerability, will also be addressed.
From Rodents to Humans: Recent Translational Advances in GLP-1–Based Therapies for Addiction
Lorenzo Leggio1
1National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224
GLP-1–based therapies have transformed obesity and diabetes care and are now generating intense interest in addiction science, given the overlap between metabolic regulation and neural circuits mediating reward, reinforcement, and stress. In this talk, Dr. Lorenzo Leggio will integrate evidence across preclinical models and emerging human data to evaluate GLP-1 receptor agonists (GLP-1RAs) as potential treatments for alcohol and other substance use disorders. Dr. Leggio will summarize animal studies showing reductions in drug intake and addiction-relevant behaviors, review real-world observational findings from health-record cohorts, and critically appraise the limited but growing randomized trial literature, including likely explanations for mixed early results and what ongoing trials are positioned to test. Dr. Leggio will conclude this lecture with key unanswered questions and critical future directions.
Structure-Based Design of Positive Allosteric Modulator of The Mu Opioid Receptor
Arghya Polley1, Teja Nikhil Peddada2, Barnali Paul1, Waruan Thotamune Kankanamalage1, Nokomis Ramos-Gonzalez1, Julio Zuarth-Gonzalez3, Chao-Cheng Kuo1, Tyler O’Brien1, Shainnel O’Eans4, Haylee Hammond4, Michael D. Cameron4, Jordan McCall1, Samuel Obeng3, Jay P. McLaughlin4, Brian K Kobilka2, Susruta Majumdar1
1Center for Clinical Pharmacology, Washington University School of Medicine, St. Louis, MO, USA 63110
2Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA 94305
3Texas Tech University Health Science Center, Amarillo, TX USA 79106
4Department of Cellular and Systems Pharmacology, College of Pharmacy, University of Florida, Gainesville, FL USA 32611
Traditional approaches that target the orthosteric site of mu opioid receptors (MOR) provide effective pain relief but can also lead to receptor overactivation and severe side effects, such as addiction and life-threatening respiratory depression. A promising alternative is to target the allosteric sites of opioid receptors by developing positive allosteric modulators (PAMs). PAMs bind outside the orthosteric pocket and modulate the activity of orthosteric agonists by enhancing endogenous pain-relief pathways and temporal selectivity, thus reducing side effects and abuse potential.
We screened a DNA-encoded library (DEL) from Hitgen to identify novel chemotypes with PAM activity at MOR. Through iterative medicinal chemistry focused on improving physicochemical properties such as cLogP, topological polar surface area (TPSA), and CNS multiparameter optimization (CNSMPO) score, we optimized our first generation hit and synthesized a library of ~40 analogs. Structure-activity relationship studies, using radioligand binding and GTP turnover assays at MOR, led to the identification of a potent candidate, AP58. AP58 showed MOR-dependent PAM actions in vitro in biochemical as well as cell-based G-protein assays as well as ex-vivo slice electrophysiology assays.
The cryo-EM structure of AP130, an iodo analog of AP58, in its G-protein-bound active state was elucidated with met-enkephalin and it showed a distinct allosteric binding site. AP58 displayed effective anti-allodynic properties in mice models of chronic constriction injury (CCI), and chemotherapy-induced peripheral neuropathy (CIPN), when administered alone in mice. In an acute thermal pain model, AP58 alone was inactive, but pretreatment potentiated the efficacy of a subtherapeutic dose of morphine.
Unlike traditional MOR agonists such as morphine and fentanyl, AP58 did not produce conditioned place preference (CPP), respiratory depression, or hyperlocomotion administered alone. While AP58 enhanced the antinociceptive effect of morphine, it did not increase side effects associated with orthosteric ligands, such as CPP, hyperlocomotion, or self-administration, suggesting that AP58 can separate analgesia from adverse effects.
In summary, we developed a novel MOR-selective PAM that may serve as a foundation for safer analgesics, and this concept could potentially be extended to other GPCRs.
The Role of Protein Dynamics in Opioid Receptor Signaling
Brian Kobilka
Department of Molecular and Cellular Physiology, Stanford University
The management of acute and chronic pain is one of the greatest challenges in modern medicine. While effective, many of the currently used opioid analgesics are highly addictive and their increased clinical use over the past 20 years is partially responsible for the opioid epidemic. The properties of more recently discovered µOR agonists suggest that it may be possible to separate analgesia from liabilities including addiction, tolerance and respiratory suppression. The µOR can signal through six G protein isoforms (Gi1,2,3, GoA,B, Gz), and through arrestin 2 and 3. We have observed that different µOR agonists differentially activate these signaling pathways. I will discuss what we have learned about the structural basis for G protein isoform and arrestin-biased signaling by the µOR.
Kratom: From a Traditional Remedy to the DEA
Christopher R. McCurdy, Ph.D., F.A.A.P.S.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Mitragyna speciosa Korth (Rubiaceae) is a tree that was first identified in Southeast Asia where the borders of Thailand and Malaysia meet. The leaves are the origin of the ethnopharmacological preparation “kratom”. Traditional use involves chewing or drinking a decoction of the leaves which results in paradoxical effects including a coca-like stimulant as well opium-like depressant actions. Traditionally, the plant extract has been used as an opium substitute, and it has been clinically used in Thailand to wean addicts off opiates. Much attention has been drawn to this recently due to the exponential increases of users in the Western world where harm has been reported. In 2016, the US DEA announced an intention to place kratom into Schedule I of the controlled substances act. This was rescinded and it was determined further research was needed before a ban. That research has exponentially increased to the point of FDA sanctioned human clinical trials. In October 2021, the 44th Expert Committee (ECDD) on Drug Dependency of the World Health Organization convened to determine if kratom should undergo ‘critical review’ for an International ban. The ECDD determined that there was inadequate evidence to recommend a critical review and kratom will be kept under surveillance.
For centuries kratom has been used to increase mood, stamina, energy, and decrease anxiety and pain. The historical use of kratom to prevent withdrawal and ween users from opioids is of great relevance to the current global opioid crisis. As kratom use has steadily increased in the United States (US), reports of adverse events have risen. It is estimated that >15 million US individuals consume kratom products. Recently, the CDC indicated poison control center calls mentioning kratom in the past couple years have skyrocketed. This may be due to the changes in product forms that started decades ago as crushed/powdered leaf that were eventually made into extracts/concentrates, and in the past few years have been sold as isolates and synthetic derivatives with only opioid activity. All of these products have simply been identified as kratom, lumping them into a single product category. In 2025 the FDA requested that the DEA consider leaving leaf material alone and place synthetically created 7-hydroxymitragynine (a trace alkaloid in traditional leaf) into Schedule I. In July 2026, the DEA announced their intent to place 7-hydroxymitragynine above certain levels, into Schedule I along with separate notice to do the same with other emerging kratom-derived synthetics.
Novel Phenyl- and Fluoro-Substituted Chiral Anandamide Probes with Exceptional Potency and Metabolic Resistance
Markos-Orestis Georgiadisa, Lipin Jia, Fei Tonga, Elena Ferrerasa, Luana Assis Ferreirab, Vuong Q. Dangc, Alexandra Faragherc, John Hainlineb, Anastasiia V. Sadybekovd, Suthakar Ganapathya, Ngan Trana, Nikolai Zvonoka, Laura M. Bohnc, Vsevolod Katritchd, Andrea G. Hohmannb, Alexandros Makriyannisa, Spyros P. Nikasa
aCenter for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
bPsychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, United States.
cDepartment of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida 33458, United States.
dDepartment of Quantitative and Computational Biology, and Department of Chemistry, Bridge Institute, Center for New Technologies in Drug Discovery and Development, University of Southern California, Los Angeles, California 90089, United States.
Building upon our chiral lipid technology, we report the development of novel anandamide analogs carrying chiral centers, fluorine atoms, and phenyl rings in judiciously chosen positions within the eicosanoid template of the endogenous N-arachidonoylethanolamine (AEA). Key successful analogs were found to exhibit remarkably high binding affinity and potency for cannabinoid receptors along with excellent stability against metabolizing enzymes.
One of our advanced molecules, namely 20,20,20-trifluoro-(R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AM12814), is the first endocannabinoid analog exhibiting unprecedented affinity for both the CB1 and CB2 receptors. In further in vitro functional characterization, AM12814 behaves as a potent, partial CB1 and CB2 agonist, thus resembling the functional profile of the physiological ligand. Our SAR results are supported by docking studies of the novel anandamide probes on the crystal structures of cannabinoid receptors. When tested in vivo, AM12814 behaves as a very potent and efficacious CB1 agonist.
Acknowledgements: National Institute on Drug Abuse (NIDA, DA009158).
Novel Approaches to Treat or Prevent Opioid Use Disorder: The Cannabis Terpene Beta-Caryophyllene and Isoform-Selective Heat Shock Protein 90 Inhibitors
John M Streicher1
1Comprehensive Center for Pain and Addiction, University of Arizona College of Medicine, Tucson, Arizona 85721, United States.
Current approaches to treat Opioid Use Disorder (OUD) are limited, have modest efficacy, and many have intrinsic abuse liability. In contrast, we’ve found that the natural product terpene Beta-Caryophyllene from Cannabis and other plants could be used to treat OUD. This molecule is extremely safe and lacks any reward liability; we showed that this drug can also prevent morphine- and fentanyl-induced place preference. We further showed that Beta-Caryophyllene does so via the Adenosine A2a Receptor in the brain, suggesting a mechanism of action via D2-MSNs in the Nucleus Accumbens.
Separately, we’ve found that isoform-selective Heat shock protein 90 (Hsp90) inhibitors selectively modulate opioid signaling in the spinal cord to enable an opioid dose-reduction strategy which could prevent OUD during therapy. These both represent separate but complementary approaches to treat OUD without the drawbacks of current therapies.
Structure-Based Design of Positive Allosteric Modulators of the Mu Opioid Receptor
Susruta Majumdar1
1Center for Clinical Pharmacology, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St Louis, MO, USA
Opioids are effective treatments for moderate to severe pain. Most currently used opiates in the clinical as well as preclinical literature target the conserved orthosteric site and lead to adverse effects like respiratory depression and addiction, limiting clinical usage in recent times.
Targeting evolutionary less conserved allosteric sites represents an alternative to developing safer pain therapeutics at the mu opioid receptor (MOR). Using DNA encoded library screening coupled with structure-based design, we report de novo design and optimization of positive allosteric modulators (PAM) at MOR as a novel strategy to design safer opioids. Our small molecule PAM label distinct sites in MOR elucidated through cryoEM structures with met-enkephalin occupying the orthosteric site. They show allosteric actions in biochemical assays, cell-based signaling assays, ex-vivo slice electrophysiology assays as well in vivo in mice. Intriguingly unlike previously described mu opioid PAMs, our lead PAM shows analgesic action administered alone in chronic pain assays suggestive PAMs potentially use the endogenous opioid system to drive pain relief.
The Temporal Binding Continuum in hMGL: Binding Order as a Pharmacological Variable
Sergiy Tyukhtenko1, Yurii Moroz2 and Alexandros Makriyannis1
1Center for Drug Discovery, Northeastern University, Boston, MA, USA.
2Enamine Ltd., Kyiv, Ukraine
Human monoacylglycerol lipase (hMGL), the primary hydrolase terminating endocannabinoid signaling by 2-arachidonoylglycerol, has long been described through static open and closed structural snapshots. Using real-time dual-nucleus (¹H/¹⁹F) NMR spectroscopy, we show that hMGL instead traverses a continuous, kinetically resolved conformational cascade—the Temporal Binding Continuum (TBC)—linking initial ligand engagement to a slow, path-dependent commitment of the lid domain.
Across a full orthosteric inhibitor panel spanning carbamates, covalent ureas, and reversible transition-state analogs, two conserved histidine reporters (His-54 and His-269) shift in chemical shift and linewidth without disappearing, establishing chemotype-independent invariant NMR fingerprinting as a general signature of orthosteric pocket occupancy. We further distinguish rapid, catalytically obligatory gating from slow, regulatory lid closure, which eliminates the His-54 signal only after allosteric engagement and is dispensable for ordinary substrate turnover.
Critically, the order in which orthosteric and allosteric ligands bind dictates the final conformational and thermodynamic outcome. Reciprocal binding-order experiments reveal a substantial free-energy asymmetry (ΔΔG° ≥ 1.38 kcal/mol) between allosteric-first and orthosteric-first engagement sequences, with orthosteric pre-occupancy write-protecting the catalytic core against allosteric-driven lid programming. This path dependence constitutes a form of conformational memory, encoded on a defined ~50-hour timescale and modulated by redox-sensitive cysteine chemistry.
These findings reframe hMGL regulation as a temporally structured, sequence-dependent process rather than a two-state equilibrium, with direct implications for inhibitor design: the order of ligand exposure—not merely occupancy—can determine whether an inhibitor achieves durable allosteric modulation or reversible orthosteric blockade. The TBC framework offers a generalizable model for path-dependent pharmacology in multi-site enzyme targets.
Acknowledgements: This research was supported by NIH (NIDA) grants T32-DA055553, R01-DA009158, DA0052271, and DA045882.
Illuminating the Monoamine Transporters Uptake 1 and 2: Development of Pharmacological Tools and Potential Therapeutics
Gisella Camacho Hernandez1
1Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States
Aberrant monoamine neurotransmission is involved in many central nervous system (CNS) diseases and disorders such as depression, attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD). To maintain monoamine homeostasis, proper function and regulation of the monoamine transporters (MATs) is necessary. MATs also known as the “uptake-1” system, are comprised by three members: the serotonin, dopamine and norepinephrine transporter (SERT, DAT and NET, respectively) and their main action is to mediate the reuptake of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) with a high affinity but low capacity.
Conversely, there is a second system known as the “uptake-2” that includes the organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT) that has low affinity but high capacity to also transport monoamines. In the last years, this uptake-2 system has arisen as an important player in monoamine clearance, especially when the uptake-1 system is impaired either pharmacologically or physiologically.
Efforts in the generation of small molecules targeting the monoamine transporters uptake 1 and 2 which include the dopamine transporter and organic cation transporter 3 will be discussed as well as their pharmacological profile and their therapeutic application.
Behavioral Assessment of the Abuse Liability of the Novel Atypical Dopamine Transporter Inhibitor UR-1-1-8
Mahfuz A. Sakib, Julio Zuarth-Gonzalez, Theophilus Torgbenu, Anushka Bhat, Sadisna Shahi, Jenny Wilkerson, Lance R. McMahon, Nadezhda German, and Samuel Obeng
Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106
Dopamine transporter (DAT) inhibitors often possess reinforcing properties that contribute to their abuse liability, making preclinical evaluation of abuse potential an important step during drug development. UR-1-1-8 is a recently developed DAT inhibitor with high affinity for DAT (15 nM), marked selectivity over the serotonin and norepinephrine transporters, and previously reported anti-inflammatory and neuroprotective effects in experimental models of multiple sclerosis. The present study examined the abuse-related behavioral profile of UR-1-1-8 using drug discrimination and intravenous self-administration procedures in Sprague-Dawley rats.
Rats were trained to discriminate 0.32 mg/kg methamphetamine. Methamphetamine produced dose-dependent increases in drug-lever responding with an ED50 of 0.146 (0.117–0.175) mg/kg, whereas cocaine fully substituted for methamphetamine with an ED50 of 1.703 (0.412–3.526) mg/kg. Modafinil also substituted for methamphetamine, exhibiting an ED50 of 113.7 (84.72–175.4) mg/kg. Although UR-1-1-8 was evaluated at doses that reduced response rates to 48.1% of vehicle, it produced a maximum of only 25% methamphetamine-lever responding and did not significantly alter the discriminative stimulus effects of methamphetamine or cocaine.
In intravenous self-administration studies, UR-1-1-8 alone failed to maintain responding above saline levels, indicating an absence of reinforcing effects. Moreover, co-administration of 0.1 mg/kg/infusion UR-1-1-8 with methamphetamine did not significantly alter the methamphetamine dose-effect function. Collectively, these findings demonstrate that UR-1-1-8 lacks methamphetamine-like discriminative stimulus effects and reinforcing efficacy, suggesting that UR-1-1-8 has substantially lower abuse liability than classical psychostimulants while remaining a promising therapeutic candidate.
Acknowledgements: Supported by Texas Tech University Health Sciences Center Office of Research and Brain Drug Discovery Center in the Jerry H. Hodge School of Pharmacy.
Troriluzole: Dual Glutamate Release Inhibitor and Glutamate Reuptake Enhancer as Therapeutic for Methamphetamine Use Disorder
Sonita Wiah1, Aryan Shekarabi1, Allen B. Reitz2, and Scott M. Rawls1,3
1Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
2Fox Chase Therapeutics Discovery, Inc., Doylestown, PA 18902
3Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
Riluzole, approved for amyotrophic lateral sclerosis (ALS), acts through a unique dual mechanism by reducing neuronal glutamate release and enhancing astrocytic glutamate reuptake, offering advantages over agents that only increase glutamate reuptake. Despite this favorable anti-glutamatergic profile for mitigating methamphetamine (METH) addiction, riluzole has pharmacokinetic (PK) liabilities that limit repurposing. To overcome these limitations, the prodrug troriluzole (TRLZ) was designed and prepared. TRLZ retains riluzole’s mechanistic profile but with optimized metabolic and PK properties (e.g., longer half-life and less PK variability). Since glutamatergic dysfunction promotes continued METH use and relapse, we tested the hypothesis that TRLZ would inhibit METH reward, reinforcement, and relapse-like behaviors in male and female adult Sprague-Dawley rats using self-administration (SA) assays. We also investigated effects of TRLZ on food SA and METH conditioned place preference (CPP). TRLZ was administered intraperitoneally (IP) in a dose range of 1–16 mg/kg.
TRLZ dose-dependently reduced acquisition of METH SA and intake under fixed ratio (FR-1) conditions and reduced reinforcing efficacy under a progressive-ratio (PR) schedule. TRLZ dose-dependently facilitated extinction of METH SA behaviors, and reduced both cue- and METH prime-induced reinstatement of seeking behaviors, with greater efficacy observed in males. In an extended METH abstinence model following 2 weeks of chronic METH SA, TRLZ reduced cue-induced seeking. TRLZ also reduced food SA, but at higher doses than those required to reduce METH SA. TRLZ also reduced acquisition and expression of METH CPP and disrupted maintenance of an established METH CPP. In vitro screening studies showed that TRLZ (riluzole) lacked binding affinity and functional activity at dopamine D1, D2, and D3 receptors, as well as at vesicular monoamine transporter 2 (VMAT2) and trace amine-associated receptor 1 (TAAR1).
In summary, TRLZ attenuated multiple core features of METH use disorder, including drug taking, motivation to obtain drug, drug seeking, and conditioned reward, with greater efficacy observed in male rats. Together with our recent demonstration of robust efficacy for TRLZ in opioid-related rat models and the current testing of TRLZ in a clinical trial for METH use disorder, these findings identify TRLZ as a potential broad-spectrum therapeutic candidate across multiple substance use disorders.
Acknowledgements: NIDA (R01 DA045499 and R41DA047169) and to Biohaven Pharmaceuticals for support and encouragement.
Unlocking Pyridazinyl Sulfonyl Chemical Space in the Discovery of Cannabinoid Receptor-1 (CB1R) CNS-Sparing Agents
Malliga R. Iyer, Ph.D1
1Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, NIAAA, National Institutes of Health (NIH), Rockville, MD, USA
Metabolic syndrome (MetS) arises from obesity and gives rise to multiple comorbidities like insulin resistance, deleterious cardiovascular events, and even organ fibrosis. Consequently, there is a pressing need for innovative drugs targeting MetS and its associated conditions. Numerous signaling pathways contribute to these chronic ailments, and the well-established endocannabinoid (EC) system is recognized for its role in modulating their pathophysiology. Primarily acting through its G-protein coupled receptors CB1 and CB2, the endocannabinoid system stands as a validated target for addressing MetS-related conditions. Specifically, the selective antagonism of central cannabinoid receptors, particularly CB1, has shown efficacy in reducing food intake, improving insulin resistance, and alleviating fibrosis.
Due to the withdrawal of rimonabant’s European approval due to psychiatric side effects, attention has shifted towards harnessing the effects of CB1 blockade utilizing CNS-sparing MoA. In this context, we have introduced a new fragment-assisted platform for generating drug-like leads based on ‘designed polypharmacology.’ This approach involves a rapid synthesis methodology and med-chem based principles to investigate the structure-activity relationships of novel heterocyclic amino compounds. The synthesis platform and detailed biological investigations including in vitro ADME, in vivo tissue distribution studies for CNS non-penetration, and efficacy studies in rodent diet-induced obesity models from this study will be presented.
Acknowledgments: This work was supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to M.R.I (ZIA AA000360). This research was supported by the Intramural Research Program of the National Institutes of Health (NIH).