Stereochemical studies of chiral H-1 antagonists of histamine: the resolution, chiral analysis, and biological evaluation of four antipodal pairs.
The resolution of the H-1 antihistamines chloropheniramine, dimethindene, carbinoxamine, and mebrophenhydramine is described. The optical purity of antipodal products is investigated by chiral HPLC (use of alpha 1-acid glycoprotein and beta-cyclodextrin columns) and NMR (spectra of beta-cyclodextrin inclusion complexes). Configurational relationships among the group are reviewed and assignments are confirmed and extended by circular dichroism evidence. Affinity constants of antipodal pairs for guinea pig ileum and cerebellum sites, determined by gut bath and binding experiments respectively, are reported together with some in vivo tests in man for central effects. Results are discussed in terms of configurational requirements for activity and variations in antipodal potency ratios within the group.
Casy
A F
AF
School of Pharmacy and Pharmacology, University of Bath, England.
Drake
A F
AF
Ganellin
C R
CR
Mercer
A D
AD
Upton
C
C
D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism
D006634:Histamine H1 Antagonists