THE EFFECTS OF SB-204070, A HIGHLY POTENT AND SELECTIVE 5-HT4 RECEPTOR ANTAGONIST, ON GUINEA-PIG DISTAL COLON

1 The pharmacology of a novel 5-HT4 receptor antagonist, SB 204070 has been evaluated in the guinea-pig isolated distal colon longitudinal m uscle-myenteric plexus (LMMP). 2 SB 204070 is a highly potent antagoni st of 5-HT-evoked cholinergically-mediated contractions in the guinea- pig distal colon. Low concentrations (10-100 pM) produced a shift to t he right of the curve (apparent pA(2) 10.8 +/- 0.1) with no significan t effect on the maximum response. With higher concentra- tions of SB 2 04070 (300 pM and above), the maximum response to 5-HT was reduced. 3 When tested against the partial 5-HT4 receptor agonist, BIMU 1, SB 204 070 was active at similar low concentrations (10 PM and above) but pro duced a reduction in maximum, with no prior shift to the right of the curve, at all concentrations tested (10-300 pM). 4 The antagonism seen with SB 204070 is unlikely to be due to a non-selective effect since high concentrations (10 nM and 1 mu M) of the compound had no effect o n cholinergically-mediated contractions evoked by the nicotinic recept or agonist, DMPP, in the same preparation. SB 204070 is unlikely to be an irreversible antagonist since the effects of the compound could be reversed upon washing of the tissue. 5 Radioligand binding studies sh ow that SB 204070 has a greater that 5000 fold selectivity for the 5-H T4 receptor over 5-HT1A, 5-HT1D, 5-HT1E, 5-HT2A, 5-HT2C, 5-HT3, GABAA( A), BDZ, TBPS, A(1) adenosine receptors, alpha(1), alpha(2), beta(1), beta(2), adrenoceptors and D-1, D-2 and D-3 dopamine receptors. 6 SB 2 04070 is a highly potent, highly selective 5-HT4 receptor antagonist a nd as such is an important new tool in evaluating the functional role of the 5-HT4 receptor.