The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound.
Prucalopride is a novel enterokinetic compound and is the 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-HT(4) receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) 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-HT(3) receptor (pK(i) 5.41) and the human sigma(1) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT(4) 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-HT(4) receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT(4) receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17), in a 5-HT(4) receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT(2A), 5-HT(2B), or 5-HT(3), motilin or cholecystokinin (CCK(1)) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 microM. It is concluded that prucalopride is a potent, selective and specific 5-HT(4) 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-HT(2A), 5-HT(2B) and 5-HT(3) receptors or motilin or CCK(1) receptors.
Briejer
M R
MR
Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Turnhoutseweg 30, 2340 Beerse, Belgium.
Bosmans
J P
JP
Van Daele
P
P
Jurzak
M
M
Heylen
L
L
Leysen
J E
JE
Prins
N H
NH
Schuurkes
J A
JA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000494:pharmacology*; D017829:Granisetron / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009037:Motilin / Q000031:analogs & derivatives / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050638:Receptors, Dopamine D4; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D012844:Sincalide / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000109:Acetylcholine; D001572:Benzofurans; D002217:Carbachol; D004146:Dioxanes; D005765:Gastrointestinal Agents; D017829:Granisetron; D007211:Indoles; D007213:Indomethacin; D009037:Motilin; D010880:Piperidines; D011949:Receptors, Cholecystokinin; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012844:Sincalide; D013449:Sulfonamides; D014665:Vasodilator Agents; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; C050802:motilin receptor; C406662:prucalopride; C084858:SB 204070A; C013087:13-Leu-motilin; C082871:GR 113808