| Abstract
| - Previous studies identified several novel tetrahydropyrimidinederivatives exhibiting muscarinicagonist activity in rat brain. Such compounds might be useful intreating cognitive and memorydeficits associated with low acetylcholine levels, as found inAlzheimer's disease. To determinethe molecular features of ligands important for binding and activity atmuscarinic receptorsubtypes, the series of tetrahydropyrimidines was extended.Several active compounds wereexamined further for functional selectivity through biochemical studiesof muscarinic receptoractivity using receptor subtypes expressed in cell lines. Severalamidine derivatives displayedhigh efficacy at m1 receptors and lower activity at m3 receptorscoupled to phosphoinositide(PI) metabolism in A9 L cells. Four ligands, including1b, 1f, 2b, and 7b,exhibited markedfunctional selectivity for m1 vs m3 receptors. Compound1f also exhibited low activity at m2receptors coupled to the inhibition of adenylyl cyclase in A9 L cells.Molecular modeling studiesalso were initiated to help understand the nature of the interaction ofmuscarinic agonistswith the m1 receptor using a nine amino model of the m1 receptor.Several importantinteractions were identified, including interactions between the estermoiety and Thr192.Additional interactions were found for oxadiazoles and alkynylderivatives with Asn382,suggesting that enhanced potency and selectivity may be achieved bymaximizing interactionswith Asp105, Thr192, and Asn382. Taken together, the data indicatethat several amidinederivatives display functional selectivity for m1 muscarinic receptors,warranting furtherevaluation as therapeutic agents for the treatment of Alzheimer'sdisease. In addition, severalamino acid residues were identified as potential binding sites for m1agonists. These datamay be useful in directing efforts to develop even more selective m1agonists.
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