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Schizophrenia is a complex disease involving the dysregulation of numerous brain circuits and patients exhibit positive symptoms (hallucinations, delusions), negative symptoms (anhedonia), and cognitive impairments. We have shown that the antipsychotic efficacy of positive allosteric modulators (PAMs) of both the M 4 muscarinic receptor and metabotropic glutamate receptor 1 (mGlu 1 ) involve the retrograde activation of the presynaptic cannabinoid type-2 (CB 2 ) receptor, indicating that CB 2 activation or potentiation could result in a novel therapeutic strategy for schizophrenia. We used two complementary assays, receptor-mediated phosphoinositide hydrolysis and GIRK channel activation, to characterize a CB 2 PAM scaffold, represented by the compound EC21a, to explore its potential as a starting point to optimize therapeutics for schizophrenia. These studies revealed that EC21a acts as an allosteric inverse agonist at CB 2 in both assays and exhibits a mixed allosteric agonist/negative allosteric modulator profile at CB 1 depending upon the assay used for profiling. A series of compounds related to EC21a also functioned as CB 2 inverse agonists. Overall, these results suggest that EC21a exhibits complicated and potentially assay-dependent pharmacology, which may impact interpretation of in vivo studies.

Medetomidine is an FDA-approved α 2 -adrenoreceptor (α 2 -AR) agonist used as a veterinary sedative due to its analgesic, sedative, and anxiolytic properties. While it is marketed for veterinary use as a racemic mixture under the brand name Domitor, the pharmacologically active enantiomer, dexmedetomidine, is approved for sedation and analgesia in the hospital setting. Medetomidine has recently been detected in the illicit drug supply alongside fentanyl, xylazine, cocaine, and heroin, producing pronounced sedative effects that are not reversed by naloxone. The pharmacological effects along with the low cost of supply and lack of regulation for medetomidine has made it a target for misuse. Since 2022, medetomidine has been found as an adulterant in samples of seized drugs, as well as in toxicological analyses of patients admitted to the emergency department after suspected overdoses across several U.S. states and Canada. This Review will discuss the history, chemistry, structure-activity relationships, drug metabolism and pharmacokinetics (DMPK), pharmacology, and emergence of medetomidine as an adulterant in drug mixtures in the context of the current opioid drug crisis.

Tianeptine ( 1 ) is an unusual antidepressant in that its mechanism of action appears to be independent from any activity at serotonin receptors or monoamine transporters. In fact, tianeptine has been shown to be a moderately potent agonist for the mu opioid receptor (MOR) and to a lesser extent the delta opioid receptor (DOR). Additionally, tianeptine's efficacy may be related to its action on glutamate-mediated pathways of neuroplasticity. Regardless of which neurotransmitter system is primarily responsible for the observed efficacy, the MOR agonist activity is problematic with respect to abuse liability. Increasing numbers of case reports have demonstrated that tianeptine is indeed being used recreationally at doses far beyond what are considered therapeutically relevant or safe, and scheduling reclassifications or outright bans on tianeptine products are ongoing around the world. It is the aim of this review to discuss the medicinal chemistry and pharmacology of tianeptine and to summarize this intriguing discrepancy between tianeptine's historical use as a safe and effective antidepressant and its emerging potential for abuse.

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M 4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace a 5-amino-2,4-dimethylthieno[2,3- d ]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M 4 and were highly brain-penetrant, the 2,4-dimethylpyrido[4',3':4,5]thieno[2,3- d ]pyrimidine tricycle core provided lead compound, VU6016235 , with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.

Herein we report progress toward a backup clinical candidate to the M 1 positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3- b ]pyridine-based M 1 PAM VU6007477 to isomeric pyrrolo[3,2- b ]pyridine and thieno[3,2- b ]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2- b ]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability in vivo screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M 1 PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M 1 activation.

Acute stimulation of M 1 or M 4 muscarinic cholinergic receptors reduces cocaine abuse-related effects in mice and rats. The combined activation of these receptor subtypes produces synergistic effects on some behavioural endpoints in mice. M 1 and M 1  + M 4 receptor stimulation in a cocaine vs. food choice assay in rats and microdialysis in rats showed delayed and lasting "anticocaine effects". Here, we tested whether these putative lasting neuroplastic changes are sufficient to occlude the reinforcing effects of cocaine at the behavioural level in mice. Mice were pre-treated with the M 1 receptor partial agonist VU0364572, M 4 receptor positive allosteric modulator VU0152100, or VU0364572 + VU0152100 two weeks prior to acquisition of cocaine intravenous self-administration (IVSA). Male C57BL/6JRj mice received vehicle, VU0364572, VU0152100, or VU0364572 + VU0152100. Female mice were tested with two VU0364572 + VU0152100 dose combinations or vehicle. To attribute potential effects to either reduced rewarding effects or increased aversion to cocaine, we tested VU0364572 alone and VU0364572 + VU0152100 in acquisition of cocaine-conditioned place preference (CPP) in male mice using an unbiased design. The acquisition of cocaine IVSA was drastically reduced and/or slowed in male and female mice receiving VU0364572 + VU0152100, but not either drug alone. Food-maintained operant behaviour was unaffected, indicating that the treatment effects were cocaine-specific. No treatment altered the acquisition of cocaine-CPP, neither in the post-test, nor in a challenge 14 days later. The cocaine IVSA findings confirm unusual long-lasting "anticocaine" effects of muscarinic M 1  + M 4 receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects., Competing Interests: Declaration of competing interest Craig W. Lindsley and P. Jeffrey Conn are inventors on multiple pending and issued patents that protect composition of matter for M(1) and M(4) receptor ligands. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

While the muscarinic acetylcholine receptor mAChR subtype 5 (M 5 ) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M 5 antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 ( 45 ) showed exquisite potency (human M 5 IC 50 = 20 nM), good subtype selectivity (>500 fold selectivity against human M 1-4 ), desirable brain exposure ( K p = 0.68, K p,uu = 0.65), and high oral bioavailability (% F > 100%). VU6036864 ( 45 ) and its close analogues will support further studies of M 5 as advanced antagonist tool compounds and play an important role in the emerging biology of M 5 .

Background: Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu 3 ) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu 3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear., Methods: We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu 3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits., Results: We first established that PCP treatment augmented excitatory transmission onto dopamine D 1 receptor-expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu 3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu 3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell., Conclusions: These data demonstrate that activation of mGlu 3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M 4 ) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2- d ]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M 4 and greatly reduced cytochrome P450 inhibition when compared with parent compound ML253 ., Competing Interests: The authors declare the following competing financial interest(s): R.A.C., S.R.B., J.L.E., M.F.L., C.W.L., P.J.C., T.M.B., D.W.E., and K.J.T. are inventors on applications for composition of matter patents that protect several series of M4 positive allosteric modulators., (© 2024 The Authors. Published by American Chemical Society.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D 4 R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D 4 R antagonists. However, developing selective D 4 R antagonists suitable for clinical translation remains a challenge.

Here, we demonstrate a structure-based small molecule virtual screening and lead optimization pipeline using a homology model of a difficult-to-drug G-protein-coupled receptor (GPCR) target. Protease-activated receptor 4 (PAR4) is activated by thrombin cleavage, revealing a tethered ligand that activates the receptor, making PAR4 a challenging target. A virtual screen of a make-on-demand chemical library yielded a one-hit compound. From the single-hit compound, we developed a novel series of PAR4 antagonists. Subsequent lead optimization via simultaneous virtual library searches and structure-based rational design efforts led to potent antagonists of thrombin-induced activation. Interestingly, this series of antagonists was active against PAR4 activation by the native protease thrombin cleavage but not the synthetic PAR4 agonist peptide AYPGKF., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Sp 3 -enriched small molecules play a critical role in developing drug candidates. While designing analogues with greater sp 3 character, a methodology utilizing a less explored cyclic-aziridine amide ring-opening reaction to generate sp 3 -enriched scaffolds has been developed and reported. This methodology enables rapid access to substructures with higher fsp 3 values, attracting greater attention within the past few decades. The reaction exhibits a wide reaction scope, featuring a highly sterically hindered phenolic ether, thiophenolic ethers, protected aniline formations, and aliphatic/heteroaromatic ring-containing aziridine amides as substrates. Additionally, this reaction provides access to congested tertiary ether formations through regioselective transformation, applicable to an extensive range of drug discovery targets, construction of complex small molecules, and natural product syntheses. The scaffolds developed show improved physicochemical properties.

Vascular smooth muscle K ATP channels critically regulate blood flow and blood pressure by modulating vascular tone and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular K ATP ) over Kir6.2/SUR1 (pancreatic K ATP ) has eluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an N -aryl- N '-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC 50 of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (>300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus vessels, VU0542270 induced ductus arteriosus constriction in a dose-dependent manner similar to that of the nonspecific K ATP channel inhibitor glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific K ATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. SIGNIFICANCE STATEMENT: Small-molecule inhibitors of vascular smooth muscle K ATP channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis; however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, this study describes the discovery and characterization of the first vascular-specific K ATP channel inhibitor, VU0542270., (Copyright © 2024 by The Author(s).)

Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT 2 ) agonists. Specifically, we examine the 5-HT 2 pharmacology of the direct indazole analogs of 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT 2 subtype selectivity for these analogs, particularly for the 5-HT 2B receptor subtype. Within this series, the potent analog VU6067416 ( 19d ) was optimized to have suitable preclinical pharmacokinetic properties for in vivo dosing, although potent 5-HT 2B agonist activity precluded further characterization for this series. Additionally, in silico docking studies suggest that the high potency of 19d may be a consequence of a halogen-bonding interaction with Phe234 5.38 in the 5-HT 2A orthosteric pocket., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)