title: Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors.
abstract: A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M(2) receptors using [(3)H]N-methylscopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a-10a and 8b-10b. The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M(1)-M(3) muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [(35)S]GTPgammaS binding assays using human M(2) receptors overexpressed in CHO cells revealed that a weak intrinsic efficacy was preserved in 8b-10b. Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixed.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Disingrini
authors.forename: Mathias
authors.initials: M
authors.lastname: Muth
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kellershohn
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D010797:Phthalimides / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000096:biosynthesis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010797:Phthalimides; D011728:Pyridones; D011976:Receptors, Muscarinic; D010095:Oxotremorine