title: Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors.
abstract: Cholinergic neurons degenerate in Alzheimer's disease, resulting in cognitive impairments and memory deficits, and drug development efforts have focused on selective M1 muscarinic agonists. 5-(3-Ethyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine trifluoroacetic acid (CDD-0102) stimulates M1 muscarinic receptors in rat brain [Messer, W.S., Jr., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl, J.J., III, Nagy, P.I., 1997a. J. Med. Chem. 40, 1230-1246.] and improves memory function in rats with lesions of the basal forebrain cholinergic system. Moreover, CDD-0102 exhibits oral bioavailability, few side effects and low toxicity, and thus represents a viable candidate for clinical studies. Despite the development of functionally selective agonists such as xanomeline and CDD-0102, there is room for improvements in ligand affinity and selectivity. The high degree of amino acid homology within transmembrane domains has hindered the development of truly selective agonists. Site-directed mutagenesis, biochemical and molecular modeling studies have identified key amino acid residues such as Thr192 and Asn382 in the binding of agonist to M1 receptors [Huang, X.P., Nagy, P.I., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1999. Br. J. Pharmacol. 126, 735-745.]. Recent work has implicated residues at the top of transmembrane domain VI in the binding of muscarinic agonists and activation of M1 receptors [Huang, X.P., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1998. J. Pharmacol. Exp. Ther. 286, 1129-1139.]. Thus, residues such as Ser388 represent molecular targets for the further development of agonists with improved M1 receptor affinity, selectivity and activity.
authors.affiliation: Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, OH 43606, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Messer
authors.forename: W G
authors.initials: WG
authors.lastname: Rajeswaran
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.forename: H J
authors.initials: HJ
authors.lastname: Zhang
authors.forename: A A
authors.initials: AA
authors.lastname: el-Assadi
authors.forename: C
authors.initials: C
authors.lastname: Dockery
authors.forename: J
authors.initials: J
authors.lastname: Liske
authors.forename: J
authors.initials: J
authors.lastname: O'Brien
authors.forename: F E
authors.initials: FE
authors.lastname: Williams
authors.forename: X P
authors.initials: XP
authors.lastname: Huang
authors.forename: M E
authors.initials: ME
authors.lastname: Wroblewski
authors.forename: P I
authors.initials: PI
authors.lastname: Nagy
authors.forename: S M
authors.initials: SM
authors.lastname: Peseckis
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D015195:Drug Design; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D016297:Mutagenesis, Site-Directed; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D008024:Ligands; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C075257:xanomeline