Absolute configuration and biological activity of mequitamium iodide enantiomers.
The enantiomers of 1-methyl-3-(10H-phenothiazine-10-ylmethyl)-1-azoniabicyclo[2 ,2,2]octane iodide (1) were prepared by chiral chromatographic resolution of the precursor mequitazine (2). The (+)-(S)-enantiomer 1b is 10-fold more potent than (-)-(R)-enantiomer 1a as a histamine antagonist, while the two enantiomers show the same antimuscarinic activity in vitro. The absolute configuration of the more active dextrorotatory isomer has been determined by X-ray analysis. Conformational analysis and molecular modeling suggest that the (+)-(S)-enantiomer can adopt a conformation similar to that attributed to the receptor binding conformers of classical antihistamines.
Di Bugno
C
C
Laboratori Guidotti S.p.A., San Piero a Grado (Pisa), Italy.
Dapporto
P
P
Giorgi
R
R
Manzini
S
S
Paoli
P
P
Subissi
A
A
Arcamone
F
F
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004347:Drug Interactions; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009904:Optical Rotation; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D001993:Bronchodilator Agents; D010640:Phenothiazines; C049967:LG 30435; D006632:Histamine; D000109:Acetylcholine