Basic and translational research ranging from animal models to pharmacological and imaging-based clinical studies of drug-addicted subjects has provided important insights into the neurobiology of addiction, resulting in the development of several investigational and approved therapeutics for patients. Yet, there remains a serious need for safe and effective drug treatments that are able to address diverse clinical addictions, as individual drugs may possess their own unique etiological fingerprint. Although the neurological mechanisms of drug addiction, and the adaptations that ensue, appear to involve many complex interactions between numerous brain regions, an overarching pathway contributing to the acute rewarding and reinforcing effects of drugs of abuse appears to involve activation of the canonical mesolimbic dopamine (DA) pathway. Indeed, antagonism of DA receptors in the nucleus accumbens (NAc), the primary structure innervated by midbrain dopaminergic neurons originating in the ventral tegmental area (VTA), severely blunts the rewarding and reinforcing effects of common drugs of abuse (e.g. psychostimulants, opiates, nicotine, and alcohol). Therefore, pharmacological modulation of drug targets that lead to inhibition of mesolimbic DA signaling has remained a focal point for strategies aimed at treating human drug addiction. Acetylcholine (ACh) is a neurotransmitter important to several physiological functions and processes in mammals, including, but not limited to nociception, motor control, and cognition. Based in part on its localization and its putative role in regulating mesolimbic and mesocortical DA circuitry, modulation of the muscarinic acetylcholine receptor subtype-5 (M5) has emerged as a potentially attractive and novel strategy for treating addiction to a wide range of drugs. In particular, studies employing the use of genetic M5-knockout mice and nonselective agonists and antagonists have implicated a role for the muscarinic receptor M5 in ACh-mediated reward and reinforcement effects of drugs of abuse. While we identified the first, and to date, only reported M5-selective ligands, the DMPK properties of these compounds rendered them unsuitable as in vivo probes. A recent high-throughput screen, employing a functional calcium fluorescence assay and recombinant M5-expressing cells, has resulted in the identification of a novel series of highly selective M5 NAMs and M5 antagonists (as well as M5 PAMs); the early in vitro and in vivo metabolism and disposition data of which indicate these series of ligands possess many characteristics common to orally bioavailable small molecules capable of engaging CNS receptors. Thus, they serve as highly promising compounds for further optimization aimed at enabling in vivo proof-of- concept studies in rodents. Moreover, they represent potential leads in the discovery of a clinical candidate for an M5 pharmacotherapy in the treatment of drug addiction.
We have leveraged our approach to exploiting 7TM receptor allosterism towards the discovery of potent and highly subtype-selective small molecule mAChR5 ligands, including negative allosteric modulators (NAMs) and antagonists of the receptor. Coupling an iterative analog medicinal chemistry strategy with contemporary approaches in the optimization of DMPK properties, we will identify bioavailable small molecule probes capable of engaging this receptor within the CNS. The systemic administration of pharmacological probes to rats will serve as a means to understand the role of M5 receptors in mesolimbic DA-mediated drug reward, as well as provide a potential basis for a novel therapeutic strategy in the treatment of human drug addiction.
