Effects of GABA(B) receptor antagonists on spontaneous and on GABA-inducedmechanical activity of guinea-pig smooth muscle preparations

The majority of GABA(B) receptor antagonists have been based on alterations of the acidic moiety of gamma -aminobutyric acid (GABA) or baclofen, such as the first selective antagonist phaclofen. More recently, a new structura l class of compounds derived by p-alkyl substitution in the phosphinic anal og of GABA, such as CGP35348 (3-amino-propyl-(diethoxymethyl)-phosphinic ac id), have been introduced as GABA(B) receptor antagonists. The present stud y examine the influence of a series of structurally related phosphinic acid analogues on mechanical activity and their effect on GABA-induced reaction s in ileal smooth muscle. In our experiments, GABA exerted a biphasic contr actile-relaxation effect with pronounced dose-dependent characteristics. 3- [[1-(S)-(3,4-Dihydrophenyl) ethyl]amino]-2-(S)-hydroxy-propyl]-(phenylmethy l)-phosphinic acid hydrochloride (CGP55845A) induced prolonged relaxation w ithout changing the phasic activity of the ileum preparations. [3-[1-R-[[2- (S)-hydroxy-3-[hydroxy-4-methoxyphenyl]-methyl]-phosphinyl]-propyl]-aminoet hyl]-benzoic acid (CGP62349) did not change the mechanical activity of smoo th muscle preparation. Trans 3-[6-[[Cyclo hexylmethyl-hydroxy-phosphinyl]-m ethyl]-3-morpholinyl]-benzoic acid (CGP71982) itself induced smooth muscle contractions. GABA(B) receptor antagonists decreased concentration-dependen tly the relaxation phase of the action of GABA from 50% to 90%. Their effec t on the contractile phase of the action of GABA was quite different-CGP558 45A decreased it dose-dependently, whereas CGP62349 and CGP71982 did not ch ange it significantly. These findings prompted us to assume that the GABA(B ) receptor antagonists studied, being phosphinic analogues, probably act on GABA(B) receptors in guinea-pig ileum smooth muscles. (C) 2001 Elsevier Sc ience BN. All rights reserved.