BIMU 8 is an agonist of 5-HT4 with Ki values of 33.9 ± 8.0 nM and 12.6 ± 0.9 nM in guinea pig ileum and striatum, respectively [1, 2].
As a member of the seven transmembrane spanning G-protein-coupled family of receptors, the 5-HT4 receptor is positively coupled to adenylate cyclase. It exists in two isoforms (5-HT4S and 5-HT4L). These two isoforms differ in the sequence and length of their carboxy termini [3].
BIMU 8 significantly decreased the K+ current in colliculi neurons. This suggested a 5-HT4 receptor-mediated effect [4]. In neurons, BIMU 8 at concentrations ranging from 0.003-0.1 µM increased EPSP amplitude but did not change membrane potential. The EPSP potentiation induced by BIMU 8 was blocked by tropisetron (1 µM), a 5-HT3/5-HT4 receptor antagonist. But ondansetron (1 µM), a 5-HT3 receptor antagonist did not blocked the EPSP potentiation induced by BIMU 8 [5].
In the hot-plate test, BIMU 8 injected i.p. in the range of doses of 20-30 mg/kg significantly induced an increase in the pain threshold. 15 min after administration, the antinociceptive effect reached a maximum and hence diminished. This effect disappeared within 45 min. Choline uptake blocker HC-3 (1 µg per mouse i.c.v.), antimuscarinic drug atropine (5 mg/kg i.p.), 5-HT4 antagonists SDZ 205-557 (10 mg/kg i.p.) and GR 125487 (20 mg/kg i.p.) completely prevented the antinociception of BIMU 8 [1].
References:
[1]. Ghelardini C, Galeotti N, Casamenti F, et al. Central cholinergic antinociception induced by 5HT4 agonists: BIMU 1 and BIMU 8. Life sciences, 1996, 58(25): 2297-2309.
[2]. Yoshikawa T, Yoshida N, Mine Y, et al. Affinity of mosapride citrate, a new gastroprokinetic agent, for 5-HT4 receptors in guinea pig ileum. The Japanese Journal of Pharmacology, 1998, 77(1): 53-59.
[3]. Hegde SS, Eglen RM. Peripheral 5-HT4 receptors. The FASEB journal, 1996, 10(12): 1398-1407.
[4]. Fagni L, Dumuis A, Sebben M, et al. The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase. British journal of pharmacology, 1992, 105(4): 973-979.
[5]. Pan H, Galligan JJ. 5-HT1A and 5-HT4 receptors mediate inhibition and facilitation of fast synaptic transmission in enteric neurons. American Journal of Physiology-Gastrointestinal and Liver Physiology, 1994, 266(2): G230-G238.