The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound

Prucalopride is a novel enterokinetic compound and is Be first representative of the benzofuran class. We set out to establish its pharmacological profile in various receptor binding and organ bath experiments. Receptor binding data have demonstrated prucalopride's high affinity to both investigated 5-HT4 receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-MT4a and 5-MT4b receptor, respectively. From the 50 other binding assays investigated in this study only the human D-4 receptor (pK(i) 5.63), the mouse 5-HT3 receptor(pK(i) 5.41) and the human sigma (i) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT4 receptor. Classical organ bath experiments were done using isolated tissues from the rat, guinea-pig and dog gastrointestinal tract, using various protocols. Prucalopride was a 5-HT4 receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50) = 7.48 +/- 0.06; insensitive to a 5-HT2A or 5-HT3 receptor antagonist, but inhibited by a 5-HT4 receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT4 receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50) = 7.81 +/- 0.17), in a 5-HT4 receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT2A, 5-HT2B, or 5-HT3, motilin or cholecystokinin (CCK,) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 muM. It is concluded that prucalopride is a potent, selective and specific 5-HT4 receptor agonist. As it is intended for treatment of intestinal motility disorders, it is important to note that prucalopride is devoid of anti-cholinergic, anticholinesterase or nonspecific inhibitory activity and does not antagonise 5-HT2A, 5-HT2B and 5-MT3 receptors or motilin or CCK, receptors. (C) 2001 Published by Elsevier Science B.V.