Structure activity relationships and problems arising from a consideration of the mechanism of action of clonidine
Rouot, B.; Leclerc, G.; Wermuth, C.G.; Miesch, F.; Schwartz, J.
Journal de Pharmacologie 8(1): 95-106
1977
ISSN/ISBN: 0021-793X Document Number: 478926
Analogues (23) related to clonidine were synthesized and their apparent partition coefficients and pKa values were measured. Several other parameters (Es, F) were calculated by means of tabulated values. The peripheral .alpha.-mimetic activity in the pithed rat, the hypotensive activity in the intact rat by i.v. and ICV values having been quantitatively correlated with some substituent constants (Es, F), These correlations allowed the prediction of activity for new compounds. Central hypotensive activity was observed for only 8 of the 23 compounds. The hypotensive activity was correlated with the parameters responsible of the peripheral .alpha.-mimetic activity. All the hypotensive compounds showed a high peripheral pD2 value, an evident local anesthetic activity and similar lipophilicity. These properties were insufficient to characterize a clonidine-like molecule, and the hypotensive activity of the phenyliminoimidazolidines does not seem to be mediated by an adrenergic mechanism.
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