Unique structure-activity relationship for 4-isoxazolyl-1,4-dihydropyridines.
A series of 4-isoxazolyl-1,4-dihydropyridines (IDs) were prepared and characterized, and their interaction with the calcium channel was studied by patch clamp analysis. The structure-activity relationship (SAR) that emerges is distinct from the 4-aryldihydropyridines (DHPs), and affinity increases dramatically at higher holding potentials. Thus, among the 3'-arylisoxazolyl analogues p-Br > p-Cl >> p-F, and p-Cl > m-Cl > o-Cl >> o-MeO. Four of the analogues were examined by single-crystal X-ray diffractometry, and all were found to adopt an O-exo conformation in the solid state. The calculated barrier to rotation, however, suggests that rotation about the juncture between the heterocyclic rings is plausible under physiological conditions. A variable-temperature NMR study confirmed the computation. With Striessnig's computational sequence homologation procedure, a working hypothesis was derived from the data that explains the unique SAR for IDs.
Zamponi
Gerald W
GW
Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
Stotz
Stephanie C
SC
Staples
Richard J
RJ
Andro
Tina M
TM
Nelson
Jared K
JK
Hulubei
Victoria
V
Blumenfeld
Alex
A
Natale
Nicholas R
NR
D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D013329:Structure-Activity Relationship
D015220:Calcium Channels; D004095:Dihydropyridines; D007555:Isoxazoles