Using grease-gap recording from rat neocortical slices, the γ-aminobutyric acid B (GABA B ) receptor agonists baclofen (3-100 μM) and SKF 97541 (3-aminopropyl-methylphosphinic acid) (1-30 μM) elicited reversible and concentration-dependent hyperpolarizing responses, with EC 5 0 values of 10 and 3 μM, respectively. The hyperpolarizations were antagonised by the GABA B receptor antagonist Sch 50911 ((+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid) (1, 5 and 10 μM). Fendiline (N-[3,3-diphenylpropyl)-α-methylbenzylamine) (5-50 μM) and its congeners, prenylamine (N-[3,3-diphenylpropyl)-α-methylphenylethylamine) (10-100 μM) and F551 (N-[3,3-diphenylpropyl)-α-methyl-3-methoxybenzylamine) (1-30 μM) reversibly enhanced hyperpolarizing responses to the agonists; such effects were reduced by Sch 50911. These arylalkylamines produced leftward shifts of the concentration-response curves, with a marked increase in the maximal hyperpolarization obtained, compared with the agonists alone, F551 being the most potent. These findings suggest that these arylalkylamines represent a new class of positive modulators of GABA B receptor-mediated function.