SYNTHESIS AND BIOLOGICAL CHARACTERIZATION OF 1,4,5,6-TETRAHYDROPYRIMIDINE AND 2-AMINO-3,4,5,6-TETRAHYDROPYRIDINE DERIVATIVES AS SELECTIVE M1 AGONISTS

Previous studies identified several novel tetrahydropyrimidine derivat ives exhibiting muscarinic agonist activity in rat brain. Such compoun ds might be useful in treating cognitive and memory deficits associate d with low acetylcholine levels, as found in Alzheimer's disease. To d etermine the molecular features of ligands important for binding and a ctivity at muscarinic receptor subtypes, the series of tetrahydropyrim idines was extended. Several active compounds were examined further fo r functional selectivity through biochemical studies of muscarinic rec eptor activity using receptor subtypes expressed in cell lines. Severa l amidine derivatives displayed high efficacy at m1 receptors and lowe r activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of a denylyl cyclase in A9 L cells. Molecular modeling studies also were in itiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 rece ptor. Several important interactions were identified, including intera ctions between the ester moiety and Thr192. Additional interactions we re found for oxadiazoles and alkynyl derivatives with Asn382, suggesti ng that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the dat a indicate that several amidine derivatives display functional selecti vity for m1 muscarinic receptors, warranting further evaluation as the rapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding site s for m1 agonists. These data may be useful in directing efforts to de velop even more selective m1 agonists.