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NEUROPHARMACOLOGY

Centrally Active Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats

Departments of Pharmacology (A.E.B., C.K.J., T.M.B., A.D.T., J.U.H., H.Y., S.B.J., J.K.S., P.J.C., C.W.L.) and Chemistry (J.P.K., M.L.B., P.R.G., H.Y., C.W.L.), Vanderbilt Program in Drug Discovery (H.Y., P.J.C., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee

Previous clinical and animal studies suggest that selective activators of M₁ and/or M₄ muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer's disease. However, highly selective centrally penetrant activators of either M₁ or M₄ have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4-chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M₄ mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M₄. VU0152099 and VU0152100 had no agonist activity but potentiated responses of M₄ to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M₄ reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M₄ plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M₄ may mimic some of the antipsychotic-like effects of less selective mAChR agonists.

Address correspondence to: Professor Craig W. Lindsley, Departments of Pharmacology and Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-6600. E-mail: craig.lindsley{at}vanderbilt.edu

This article has been cited by other articles:

				J. E. Marlo, C. M. Niswender, E. L. Days, T. M. Bridges, Y. Xiang, A. L. Rodriguez, J. K. Shirey, A. E. Brady, T. Nalywajko, Q. Luo, et al. Discovery and Characterization of Novel Allosteric Potentiators of M1 Muscarinic Receptors Reveals Multiple Modes of Activity Mol. Pharmacol., March 1, 2009; 75(3): 577 - 588. [Abstract] [Full Text] [PDF]