5-Amino-3,4-dimethyl-thieno[2,3-c]pyridazine-6-carboxylic acid 4-trifluoromethanesulfonyl-benzylamide

VU0467154 is a positive allosteric modulator of the M₄ muscarinic acetylcholine receptor that potentiates acetylcholine responses in CHO cells expressing M₄ receptors (EC₅₀s = 17.7, 630, and 1,000 nM for rat, human, and cynomolgus monkey receptors, respectively). It is selective for M₄ over M_1-3 and M₅ receptors and a panel of receptors, transporters, and cation channels when used at a concentration of 10 μM. In vivo, VU0467154 (3-56.6 mg/kg, p.o.) reverses amphetamine-induced hyperlocomotion in rats. It reverses MK-801-induced hyperlocomotion, deficits in a pairwise visual discrimination task, and impairments in the acquisition of contextual fear conditioning in wild-type, but not M₄ knockout, mice. VU0467154 (3-30 mg/kg) also increases freezing behavior in contextual and tone fear conditioning tests in wild-type mice when administered prior to the conditioning session. Chronic administration of VU0467154 (10 mg/kg once daily) reduces motor incoordination and prevents decreases in locomotion in the YAC128 transgenic mouse model of Huntington''s disease.