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Project #4 (PI: P. Jeffery Conn, Ph.D.): Highly Selective Muscarinic Agents as Antiparkinsonian Therapy

Overview

Cholinergic neurons provide important neuromodulatory control of the basal ganglia (BG) motor circuit. Interestingly, muscarinic acetylcholine receptor (mAChR) antagonists were the first available treatments for PD and can have robust clinical efficacy.  Unfortunately, clinical utility of these compounds is limited by severe central and peripheral side effects. It is likely that the adverse effects of mAChR antagonists are due to the fact that available compounds are non-selective and have similar antagonists potencies at all of the 5 mAChR subtypes (termed M1-M5).  Development of an understanding of the individual mAChR subtypes involved in modulating BG function could provide a basis for development  mAChR antagonists that selectively block individual mAChR subtypes and may have antiparkinsonian efficacy with reduced adverse effect liability compared with the non-selective mAChR antagonists.

VU0357017 effectsVU0357017 effects 2

Previous efforts to develop highly selective ligands for individual mAChR subtypes have failed.  Thus, definitive assessment of the physiological roles of individual mAChR subtypes and development of highly subtype-selective mAChR antagonists for therapeutic use has not been possible.  The previous inability to achieve high selectivity for individual mAChRs is due to the high conservation of the orthosteric acetylcholine (Ach) site and an inability to specifically target the ACh subtype on individual mAChRs.  Over the past 3 years, we have made major breakthroughs in discovery and characterization of novel compounds that are highly selective for individual mAChR subtypes.  A key to this success has been a strategy of targeting allosteric sites on mAChRs rather than developing ligands that act at the highly conserved orthosteric ACh binding site.  We now have developed highly selective ligands for three major mAChR subtypes, M1, M4, and M5, each of which is thought to play important roles in regulating BG function.  For instance, Figure 1 shows the effect of a novel allosteric agonist of M1, termed VU0357017, in cell lines expressing each of the 5 mAChR subtypes (M1-M5).  VU0357017 has robust agonist activity at M1 receptors but has no detectable activity at M2 - M5 receptors.  Another exciting advance came with the discovery of VU0255035 as a highly selective M1 antagonist. VU0255035 induces a complete concentration-dependent inhibition of the response of M1 to Ach, but only weakly inhibits M2 at high concentrations, and has little effect at M3-M5 (Fig. 2). We have also developed pharmacological reagents that are highly selective for M4 or M5. In addition to these subtype-selective mAChR ligands, we now have access to a panel of knockout mice in which each of the individual mAChR subtypes has been individually deleted. Discovery of mAChR subtype-selective ligands along with M1 - M5 knockout mice provides an unprecedented opportunity to establish the roles of individual mAChR subtypes in regulation of BG function and potential antiparkinsonian effects of subtype-selective mAChR antagonists.  

Aims

Recent studies suggest that many of the mAChR effects on BG function may be due to actions in the subthalamic nucleus (STN) and substantia nigra pars reticulate (SNr).  In addition, recent evidence suggests that mAChRs may modulate activity of dopamine neurons in the substantia nigra pars compacta (SNc).  In this project, we will perform a series of studies in which we systematically evaluate the roles of individual mAChR subtypes in regulating STN and substantia nigra function.  Specifically, we will test the hypothesis that activation of M1 has excitatory effects on STN and SNr projection neurons and that activation of M4 reduces inhibitory synaptic transmission in both of these regions.  If so, blockade of M1 and M4 in these regions could contribute to the antiparkinsonian effects of mAChR antagonists.  We will also test the hypothesis that activation of M5 has excitatory effects on dopamine neurons in the SNc.   If so, blockade of M5 could reduce the overall antiparkinsonian effects of non-selective mAChR antagonists.  Also, selective activators of this receptor could have antiparkinsonian effects early in the course of PD when substantial numbers of dopamine neurons still survive.  Finally, we will test the hypothesis that selective antagonists of M1 and M4 and a selective M5 allosteric activator have antiparkinsonian effects in rodent models. 

Quicklinks for Dr. Conn:
The Conn Lab
The Vanderbilt Center for Neuroscience Drug Discovery
Dr. Conn's Recent Publications