SELECTIVE AND FUNCTIONAL 5-HYDROXYTRYPTAMINE(4) RECEPTOR ANTAGONISM BY SB-207266

1 The pharmacology of a novel 5-HT4 receptor antagonist, SE 207266 has been evaluated in vitro in the guinea-pig distal colon longitudinal m uscle myenteric plexus (LMMP) and in vivo in the dog Heidenhain pouch. 2 SE 207266 is a highly potent antagonist of 5-HT-evoked, cholinergic ally-mediated contractions in the guinea-pig distal colon. Low concent rations (0.1-10 nM) produced a parallel shift to the right of the conc entration-effect curve (apparent pA(2) 10.6+/-0.1) with no significant effect on the maximum response. With higher concentrations of SE 2072 66 (30 nM and above) the maximum response to 5-HT was reduced. 3 The a ntagonism seen with SE 207266 cannot be attributed to a non-selective effect since high concentrations (1 mu M) had no effect on cholinergic ally-mediated contractions evoked by the nicotinic receptor agonist DM PP in the same preparation. 4 SE 207266 is not an irreversible antagon ist since the effects of the compound were reversible upon washing of the tissue. 5 In the dog Heidenhain pouch, oral (0.1-100 mu g kg(-1)) and intravenous (0.1-100 mu g kg(-1)) administration of SE 207266 prod uced a dose-dependent antagonism of the contractions evoked by a bolus intravenous injection of 5-HT. An ID50 for SE 207266 of 1.3 mu g kg(- 1) was obtained following i.v. administration and 9.6 mu g kg(-1) foll owing oral administration. 6 The antagonistic effects of SE 207266 (0. 1-100 mu g kg(-1)) in the dog Heidenhain pouch were long lasting since , following oral administration, the response to 5-HT was reduced for at least 135 min. 7 SE 207266 is a highly potent, highly selective and orally active 5-HT4 receptor antagonist. This compound is the first o rally active amide to be identified in this class of antagonists and a s such is an important new tool in the evaluation of 5-HT4 receptor fu nction both in vitro and in vivo.