[Potassium channel activators: comparative structural study of pinacidil, diazoxide and cromakalim].
A conformational analysis has been performed with SYBYL starting from the energy optimized (Tripos force field) X-ray conformation of (R,S)-pinacidil. The geometry of four selected low energy conformers has been reoptimized using the AM1 semiempirical Molecular Orbital method (MOPAC 5.0), and the total energy of the optimized conformers has been compared. In spite of an apparent structural dissimilarity, a good analogy has been found between the calculated isopotential map of diazoxide and that of at least one selected low energy conformer of pinacidil. It has been suggested that, unlike cromakalim, the low but observable activity of pinacidil on pancreatic B-cells could be explained by adoption for this compound of a conformation having a diazoxide-like stereoelectronical imprint which could assume a similar interaction on the same biological receptor.
Dupont
L
L
Institut de Physique, Université de Liège, Sart-Tilman.
Pirotte
B
B
de Tullio
P
P
Masereel
B
B
Delarge
J
J
D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D019806:Cromakalim; D003981:Diazoxide / Q000737:chemistry*; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D020110:Pinacidil; D015221:Potassium Channels / Q000819:agonists*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology
D000959:Antihypertensive Agents; D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D020110:Pinacidil; D003981:Diazoxide