Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats.
Previous clinical and animal studies suggest that selective activators of M(1) and/or M(4) 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 M(1) or M(4) 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 M(4) 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 M(4). VU0152099 and VU0152100 had no agonist activity but potentiated responses of M(4) 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 M(4) 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 M(4) plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M(4) may mimic some of the antipsychotic-like effects of less selective mAChR agonists.
Brady
Ashley E
AE
Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.
Jones
Carrie K
CK
Bridges
Thomas M
TM
Kennedy
J Phillip
JP
Thompson
Analisa D
AD
Heiman
Justin U
JU
Breininger
Micah L
ML
Gentry
Patrick R
PR
Yin
Huiyong
H
Jadhav
Satyawan B
SB
Shirey
Jana K
JK
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D004298:Dopamine; D008636:Mesencephalon; D009043:Motor Activity / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D013876:Thiophenes / Q000494:pharmacology*
C579414:3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno(2,3-b)pyridine-2-carboxamide; D011725:Pyridines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; D000109:Acetylcholine; D004298:Dopamine
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