title: DFT calculation of four new potential agents muscarinic of bispyridinium type: structure, synthesis, biological activity, hydration, and relations with the potents W84 and DUO-3O.
abstract: Four new potential agents muscarinic (allosteric modulators) were synthesized and studied by using the B3LYP density functional method. The optimum conformation and geometry structure of these compounds were determined and analyzed. Solvent effects were considered including a variable number (1-15) of explicit water molecules surrounding the compound in order to simulate the first hydration shell, as well as using the Tomasi's polarized continuum model (PCM). A similar simultaneous analysis of the potents W84 and DUO-3O allosteric modulator of muscarinic receptors was also carried out. The effect of the hydration on the total atomic charges and several intermolecular distances of interest were also discussed. The biological activity against acetylcholine of our four synthesized bispyridinium salts was determined. Relationships/tendencies structure-activity were established. Several general conclusions were underlined.
authors.affiliation: Departamento de Química-Física I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain. alcolea@quim.ucm.es
authors.forename: M
authors.initials: M
authors.lastname: Alcolea Palafox
authors.forename: P
authors.initials: P
authors.lastname: Posada-Moreno
authors.forename: A L
authors.initials: AL
authors.lastname: Villarino-Marín
authors.forename: C
authors.initials: C
authors.lastname: Martinez-Rincon
authors.forename: I
authors.initials: I
authors.lastname: Ortuño-Soriano
authors.forename: I
authors.initials: I
authors.lastname: Zaragoza-García
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D000494:Allosteric Regulation; D000818:Animals; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D019295:Computational Biology; D005260:Female; D008968:Molecular Conformation; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000187:drug effects; D012545:Schiff Bases / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018678:Cholinergic Agents; C558229:DUO 3O; D010797:Phthalimides; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D011976:Receptors, Muscarinic; D012545:Schiff Bases; C558228:W84 compound; D000109:Acetylcholine