title: Deoxamuscaroneoxime derivatives as useful muscarinic agonists to explore the muscarinic subsite: demox, a modulator of orthosteric and allosteric sites at cardiac muscarinic M2 receptors.
abstract: A series of muscarinic agonists, straight chained, branched, cyclic alkyl and aromatic derivatives of the oxime 1 (demox) was designed with the aim of investigating their activity on muscarinic receptor subtypes. Effects on M1 receptor were assessed functionally by a microphysiometer apparatus, while M2, M3, and M4 receptor potency and affinity were studied on isolated preparations of guinea pig heart, ileum, and lung, respectively. The results suggest that the substitution of a hydrogen with a long side-chain or bulky group generally induces a decrease in potency at M1 and M3 subtypes, while a general increase in this parameter is obtained at M2 subtype. Among the agonists 2-18, compound 4 behaves as a full agonist with a preference for M3 subtype. Moreover, compound 12 is inactive at M1 and M4 receptors while it displays a full agonist activity at M2 and M3 subtypes. Since demox displays a variable response on cardiac M2 receptors regulating heart force, an in-depth inquiry of the functional behaviour of this compound was carried out at M2 receptors. In presence of 10(-11) and 10(-10) M demox, the binding of [3H]-NMS was increased by approximately 30% as a consequence of an increase of the association of [3H]-NMS to membranes; this effect was not observed in presence of a higher concentration of [3H]-NMS. Higher concentrations of demox decreased the binding of [3H]-NMS to heart atrial membranes but significantly retarded the dissociation of this radioligand. Our results suggest that demox may interact with orthosteric and allosteric sites of atrial M2 muscarinic receptor.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, MC, Italy. angeli@camserv.unicam.it
authors.forename: Piero
authors.initials: P
authors.lastname: Angeli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
authors.forename: Franco
authors.initials: F
authors.lastname: Cantalamessa
authors.forename: Cinzia
authors.initials: C
authors.lastname: Nasuti
authors.forename: Francesca
authors.initials: F
authors.lastname: Novi
authors.forename: Roberto
authors.initials: R
authors.lastname: Maggio
authors.forename: Ahmed R
authors.initials: AR
authors.lastname: Qasem
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009116:Muscarine / Q000031:analogs & derivatives / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018721:Muscarinic Agonists; D010091:Oximes; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C449979:demox; D009116:Muscarine