Comparative activities of the enantiomeric GABA(B) receptor agonists CGP 44532 and 44533 in central and peripheral tissues

In neocortical slices maintained in Mg2+-free Krebs medium, the gamma -amin obutyric acid (GABA(B)) receptor agonists baclofen, (3-amino-2(S)-hydroxypr opyl)methylphosphinic acid (CGP 44532), and its (R)-enantiomer CGP 44533 de pressed the frequency of spontaneous discharges in a concentration-dependen t manner (EC50 = 10, 6.5, and 50 muM, respectively). These effects were rev ersibly antagonised by the GABA(B) receptor antagonist (+)-(S)-5,5 dimethyl morpholinyl-2-acetic acid (Sch 50911) (3, 10, and 30 muM) (average pA(2) va lue = 6.0 +/- 0.2). In neocortical wedges, baclofen, CGP 44532 and CGP 4453 3 elicited concentration-dependent hyperpolarisations (the EC(50)s were 14, 7.5 and 16 muM, respectively) sensitive to Sch 50911 (1, 5, 10 muM) (avera ge pA(2) value = 6.0 +/- 0.1), whilst they also depressed ileal electricall y elicited cholinergic twitch contractions (EC50 = 11, 7, and 50 muM) that were antagonised by Sch 50911 (average pA(2) value = 6.0 +/- 0.1). In elect rically stimulated brain slices preloaded with [H-3]GABA, baclofen, CGP 445 32 and CGP 44533 decreased [H-3]GABA release (IC50 = 5, 0.45, and 10 muM); this effect was reversed by Sch 50911 (50 muM). It is concluded that CGP 44 532 is a far more potent agonist at GABA(B) autoreceptors than at central o r peripheral heteroreceptors. (C) 2001 Published by Elsevier Science B.V.