The National Institute on Drug Abuse (NIDA) defines drug addiction as a chronic, often relapsing brain disease that causes compulsive drug seeking and use, despite harmful consequences to the addicted individual and to those around him or her. The mesolimbic dopaminergic system is the key circuitry involved in the rewarding properties associated with drug of abuse. Dopaminergic neurons with cell bodies in the ventral tegmental area (VTA) of the midbrain project towards the limbic forebrain, chiefly to the nucleus accumbens (NA).[1, 2]
Several studies have indicated that M5 muscarinic receptors are expressed on the dopaminergic neurons in the VTA and are involved in establishing the drug rewarding properties in the mice.[32, 33] Moreover, the M5 receptor knockout mice (M5-/-) studies showed a decreased dependence on the drug of abuse.[3] Given the evidence of M5 muscarinic receptor involvement in the development of drug dependence, antagonists targeting these receptors present a unique tool to tackle the problem of drug addiction.
Preliminary studies identified the fumarate salt of 2-(4-methoxy-1,2,5-thiadiazol-3-yloxy)-N,N-dimethylethanamine, compound 1, as a promising lead compound for its ability to inhibit the stimulation of carbachol, a known muscarinic agonist, at the M5 muscarinic receptors in a dose dependent manner. Therefore, based on compound 1 and other known compounds exhibiting selectivity for muscarinic M5 receptor subtype namely, amiodarone[36], VU0238429[37], VU0365114 and VU0400265[38], a general scaffold for M5 muscarinic antagonists was designed.
Subsequently, a retro-synthetic pathway was designed in order to synthesize a series of compounds with possible antagonistic action at the M5 muscarinic receptors. Following synthesis, the compounds were characterized for their activity at the M5 muscarinic receptor using the phosphatidyl inositol (PI) turnover assay.[4] In order to determine the antagonistic properties of the synthesized compounds, the effects of CDD compounds (1µM and 100µM) on the EC80 concentration of acetylcholine were also studied. The studies identified a few compounds that were able to alter the response of acetylcholine at M5 muscarinic receptors and helped characterized structure activity relationships for a M5 muscarinic receptor antagonist. These studies form the groundwork for future efforts focused on developing selective muscarinic antagonists for the treatment of drug abuse.