title: VB20B7, a novel 5-HT-ergic agent with gastrokinetic activity. I. Interaction with 5-HT3 and 5-HT4 receptors.
abstract: This study describes the in-vitro interaction of the gastrokinetic agent 2[1-(4-piperonyl)piperazinyl]benzothiazole (VB20B7) with the 5-hydroxytryptamine 5-HT3 and 5-HT4 receptor subtypes, using functional as well as radioligand binding studies. The benzamide derivative cisapride was used as a comparison. In radioligand binding assays VB20B7 showed, like cisapride, a weak affinity at 5-HT3 receptors from rat cerebral cortex. The new compound lacked any affinity at other 5-HT receptors or at dopaminergic D2 receptors, whereas cisapride showed high affinity for the 5-HT4 receptors from guinea-pig hippocampus and moderate affinity at dopaminergic D2 receptors. In the non-stimulated guinea-pig ileum, the concentration-response curves to the specific 5-HT3 agonist 2-Me-5-HT and to 5-HT were shifted to the right by VB20B7. In the rat oesophagus tunica muscularis mucosae preparation (TMM), VB20B7 was evaluated for its activity at 5-HT4 receptors. VB20B7 behaved as a 5-HT4 receptor agonist, inducing a concentration-dependent relaxation of the preparation precontracted with carbachol. In this preparation, VB20B7 and cisapride were able to stimulate adenylate cyclase activity, an effect probably mediated through activation of 5-HT4 receptors, as can be inferred from the blockade by the 5-HT4 antagonist, tropisetron, of the enhanced cAMP formation. However, consistent with the lack of affinity at central 5-HT4 receptors, VB20B7 did not stimulate cAMP formation in guinea-pig hippocampal slices. VB20B7 also caused an increase in the twitch response of the transmurally stimulated guinea-pig ileum, although at a concentration higher than cisapride. This effect was blocked by desensitization of the 5-HT4 receptor with 5-MeOT and also by the 5-HT4 receptor antagonist tropisetron. Both VB20B7 and cisapride increased the K(+)-evoked acetylcholine release in this preparation. The results show that VB20B7 possesses affinity for 5-HT4 receptors located in the rat TMM and guinea-pig ileum preparations, but is devoid of affinity at central 5-HT4 receptors. In addition, VB20B7 shows low to moderate affinity at both central and peripheral (enteric) 5-HT3 receptors. The interaction of VB20B7 with the peripheral 5-HT4 and 5-HT3 receptors may be relevant for the gastrokinetic effects of the new compound.
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ramirez
authors.forename: E
authors.initials: E
authors.lastname: García-Garayoa
authors.forename: G
authors.initials: G
authors.lastname: Romero
authors.forename: A
authors.initials: A
authors.lastname: Monge
authors.forename: J
authors.initials: J
authors.lastname: Roca
authors.forename: J
authors.initials: J
authors.lastname: Del Río
authors.forename: B
authors.initials: B
authors.lastname: Lasheras
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D005765:Gastrointestinal Agents; D010879:Piperazines; D011985:Receptors, Serotonin; D013844:Thiazoles; C087141:2-(1-(4-piperonyl)piperazinyl)benzothiazole; D002217:Carbachol; D000242:Cyclic AMP