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: W S Messer Jr, W G Rajeswaran, Y Cao, H J Zhang, A A el-Assadi, C Dockery, J Liske, J O'Brien, F E Williams, X P Huang, M E Wroblewski, P I Nagy, S M Peseckis
• Journal: Pharmaceutica acta Helvetiae (Pharm Acta Helv) Vol. 74 Issue 2-3 Pg. 135-40 (Mar 2000) ISSN: 0031-6865 [Print] Switzerland
• PMID: 10812950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Ligands
• Muscarinic Agonists
• Pyridines
• Receptor, Muscarinic M1
• Receptors, Muscarinic
• Thiadiazoles
• xanomeline

Topics

• Alzheimer Disease (drug therapy, genetics)
• Animals
• Drug Design
• Injections, Intraperitoneal
• Ligands
• Male
• Models, Molecular
• Muscarinic Agonists (chemical synthesis, pharmacology, therapeutic use)
• Mutagenesis, Site-Directed
• Pyridines (chemical synthesis, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Muscarinic M1
• Receptors, Muscarinic (chemistry, drug effects, genetics)
• Thiadiazoles (chemical synthesis, pharmacology, therapeutic use)