Pteropodine and isopteropodine are heteroyohimbine-type oxindole alkaloid components of Uncaria tomentosa (Willd.) DC, a Peruvian medicinal plant known as cat’s claw. In this study, the effects of these alkaloids on the function of Ca2+ -activated Cl currents evoked by stimulation of G protein-coupled muscarinic M1 acetylcholine and 5-HT2 receptors were studied in Xenopus oocytes in which rat cortex total RNA was translated. Pteropodine and isopteropodine (1 – 30 AM) failed to induce membrane current by themselves. However, these alkaloids markedly enhanced the current responses evoked by both acetylcholine and 5-hydroxyhyptamine (5-HT) in a concentration-dependent and reversible manner with the maximal effects at 30 AM. Pteropodine and isopteropodine produced 2.7- and 3.3-fold increases in the acetylcholine response with EC50 values of 9.52 and 9.92 AM, respectively, and 2.4- and 2.5-fold increases in the 5-HT response with EC50 values of 13.5 and 14.5 AM, respectively. In contrast, in oocytes injected with total RNA from the rat cerebellum or spinal cord, neither alkaloid had an effect on the metabotropic current responses mediated by glutamate receptor1 and 5 (mGlu1/5) receptors or ionotropic responses mediated by N-methyl-D-aspartate, kainic acid or glycine. Pteropodine and isopteropodine (10 AM) significantly reduced the EC50 values of acetylcholine and 5-HT that elicited current responses, but had no effect on the maximal current responses elicited by acetylcholine and 5-HT. On the other hand, mitraphylline, a stereoisomer of pteropodine, failed to modulate acetylcholine- and 5-HT-induced responses. These results suggest that pteropodine and isopteropodine act as positive modulators of muscarinic M1 and 5-HT2 receptors. D 2002 Elsevier Science B.V. All rights reserved.