Verapamil analogues with restricted molecular flexibility: synthesis and pharmacological evaluation of the four isomers of alpha-[1-[3-[N-[1- [2-(3,4-dimethoxyphenyl)ethyl]]-N-methylamino]cyclohexyl]]-alpha- isopropyl-3,4-dimethoxybenzene-acetonitrile.
The synthesis and pharmacological activities of the four isomeric racemates of alpha-[1-[3-[N-[1-[2-(3,4-dimethoxyphenyl)ethyl]]-N- methylamino]cyclohexyl]]-alpha-isopropyl-3,4-dimethoxybenzene-acetoni trile are reported (2a-d). The compounds are verapamil analogues with restricted molecular flexibility designed to gather information on the active conformation(s) of the parent drug. The relative stereochemistry of the four racemates was established by X-ray crystallography and by 1H NMR spectroscopy; conformational analysis was supported by theoretical calculations. Negative inotropic and chronotropic activities were evaluated on guinea pig atria, while vasodilatory activity on smooth muscle was tested on guinea pig aortic strips. Binding studies on cat ventricles were performed using (-)-[N-methyl-3H]desmethoxyverapamil (D888) as a reference ligand. The results seem to support the hypothesis that cardiac depressant and vasorelaxant activities are due to different conformations of the verapamil molecule.
Dei
S
S
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Romanelli
M N
MN
Scapecchi
S
S
Teodori
E
E
Gualtieri
F
F
Chiarini
A
A
Voigt
W
W
Lemoine
H
H
D000097:Acetonitriles / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016275:Atrial Function; D002415:Cats; D006224:Cricetinae; D003864:Depression, Chemical; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009200:Myocardial Contraction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry; D014961:X-Ray Diffraction
D000097:Acetonitriles; D000840:Anisoles; C080794:alpha-(1-(3-(N-(1-(2-(3,4-dimethoxyphenyl)ethyl))-N-methylamino)cyclohexyl))-alpha-isopropyl-3,4-dimethoxybenzeneacetonitrile; D014700:Verapamil