Verapamil analogues with restricted molecular flexibility.
Three analogues with restricted flexibility were designed to study the active conformation of verapamil during interaction with the slow calcium channel. Thus cis- and trans-1-(3,4-dimethoxyphenyl)-4-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N- methylamino]-r-1-cyclohexanecarbonitrile (5a and 5b), and 4-(3,4-dimethoxyphenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-cyanopiper idine, in which the verapamil structure is inserted into a cyclohexane or piperidine ring, were synthesized. Conformational analysis was performed with NMR and theoretical methods, and slow calcium channel antagonism was tested on guinea pig aorta strips. The compounds are some 100 times less potent than the parent compound even if they are able to reach conformations that are quite close to the lowest energy conformation proposed for verapamil and similar compounds. It appears that the flexibility to rotate around the bond between the quaternary atom and the adjacent methylene, a property which is lost in compounds 5a, 5b, and 6, is a major requisite for the calcium antagonism of verapamil.
Dei
S
S
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Romanelli
M N
MN
Scapecchi
S
S
Teodori
E
E
Chiarini
A
A
Gualtieri
F
F
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry
D002121:Calcium Channel Blockers; D014700:Verapamil