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

Prucalopride is a novel enterokinetic compound and is Be first representati ve of the benzofuran class. We set out to establish its pharmacological pro file in various receptor binding and organ bath experiments. Receptor bindi ng 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 th e 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 i solated tissues from the rat, guinea-pig and dog gastrointestinal tract, us ing various protocols. Prucalopride was a 5-HT4 receptor agonist in the gui nea-pig colon, as it induced contractions (pEC(50) = 7.48 +/- 0.06; insensi tive to a 5-HT2A or 5-HT3 receptor antagonist, but inhibited by a 5-HT4 rec eptor antagonist) as well as the facilitation of electrical stimulation-ind uced 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. Prucalop ride 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 re ceptor agonist. As it is intended for treatment of intestinal motility diso rders, it is important to note that prucalopride is devoid of anti-choliner gic, anticholinesterase or nonspecific inhibitory activity and does not ant agonise 5-HT2A, 5-HT2B and 5-MT3 receptors or motilin or CCK, receptors. (C ) 2001 Published by Elsevier Science B.V.