title: Synthesis, pharmacological effects, and conformation of 4,4-disubstituted 1,4-dihydropyridines.
abstract: 4,4-Disubstituted 1,4-dihydropyridines are synthesized by intramolecular addition of sulfinyl carbanions to pyridines. These disubstituted derivatives show a loss of Ca antagonistic potency of up to three powers of 10 both in vitro on aortic rings and in vivo on anaesthetized dogs as compared to examples that are monosubstituted at the 4-position of the DHP ring. As the X-ray structure shows, the 4-aryl substituent is present not in the accustomed axial conformation, but in an equatorial one. This dramatic change in conformation could be the reason for the major loss of activity and would indicate the need for axial conformation of the aryl residue in pharmacologically active 1,4-dihydropyridines. The change in conformation was also confirmed by quantum chemical calculations (AM1).
authors.affiliation: Bayer AG, Pharma-Forschungszentrum, Wuppertal, FRG.
authors.forename: S
authors.initials: S
authors.lastname: Goldmann
authors.forename: L
authors.initials: L
authors.lastname: Born
authors.forename: S
authors.initials: S
authors.lastname: Kazda
authors.forename: B
authors.initials: B
authors.lastname: Pittel
authors.forename: M
authors.initials: M
authors.lastname: Schramm
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D008958:Models, Molecular; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000959:Antihypertensive Agents; D004095:Dihydropyridines; C033710:1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester; D009543:Nifedipine