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Abstract

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 Alzheimer9s 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-<i>N</i>-(4-chlorobenzyl)-4, 6-dimethylthieno[2,3-<i>b</i>]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-<i>N</i>-(benzo[d][1,3]dioxol-5-ylmethyl)-4,6-dimethylthieno[2,3-<i>b</i>]pyridine carboxamide] and VU0152100 [3-amino-<i>N</i>-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-<i>b</i>]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.