Effects of GABA(B) receptor antagonists on spontaneous and on GABA-induced mechanical 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 structural class of compounds derived by p-alkyl substitution in the phosphinic analog of GABA, such as CGP35348 (3-amino-propyl-(diethoxymethyl)-phosphinic acid), have been introduced as GABA(B) receptor antagonists. The present study examine the influence of a series of structurally related phosphinic acid analogues on mechanical activity and their effect on GABA-induced reactions in ileal smooth muscle. In our experiments, GABA exerted a biphasic contractile-relaxation effect with pronounced dose-dependent characteristics. 3-[[1-(S)-(3,4-Dihydrophenyl) ethyl]amino]-2-(S)-hydroxy-propyl]-(phenylmethyl)-phosphinic acid hydrochloride (CGP55845A) induced prolonged relaxation without changing the phasic activity of the ileum preparations. [3-[1-R-[[2-(S)-hydroxy-3-[hydroxy-4-methoxyphenyl]-methyl]-phosphinyl]-propyl]-aminoethyl]-benzoic acid (CGP62349) did not change the mechanical activity of smooth muscle preparation. Trans 3-[6-[[Cyclo hexylmethyl-hydroxy-phosphinyl]-methyl]-3-morpholinyl]-benzoic acid (CGP71982) itself induced smooth muscle contractions. GABA(B) receptor antagonists decreased concentration-dependently the relaxation phase of the action of GABA from 50% to 90%. Their effect on the contractile phase of the action of GABA was quite different-CGP55845A decreased it dose-dependently, whereas CGP62349 and CGP71982 did not change 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.