COMPARISON OF 5-HT4 RECEPTORS IN GUINEA-PIG COLON AND RAT ESOPHAGUS -EFFECTS OF NOVEL AGONISTS AND ANTAGONISTS

5-HT4 receptors in isolated distal colon myenteric plexus of guinea-pi g, mediating contraction of longitudinal smooth muscle, have been furt her characterized by selective agonists and antagonists. The indole ag onists, 5-HT and 5-methoxytryptamine (5-MeOT), were full agonists (rel ative to 5-HT) with potency values (pEC(50)) of 8.0 +/- 0.1 (n = 50) a nd 7.8 +/- 0.1(n = 12), respectively. 5-HT4 receptor agonists of other structural classes, including benzimidazolones (BIMU 1 and BIMU 8), a nd benzamides ((S)-zacopride, (R)-zacopride, renzapride, SC 49518) wer e partial agonists with intrinsic activities less than that of 5-HT. I n general , the potencies for these compounds at 5-HT4 receptors media te relaxation. GR 113808 peridinyl]methyll-methyl-1H-indole-3-carboxyl ate}, RS 39604 ybenzyloxy)phenyl]-3-[1-[2-[(methylsulfonyl)amino] ethy l]-4-piperidinyl]-1-propanone hydrochloride and SB 204070 {(1-n-butyl- 4-piperidinyl)methyl 8-amino-7-chloro-1,4-benzodioxane-5-carboxylate} antagonized 5-HT responses with pA(2) values of 9.1 +/- 0.1, 9.0 +/- 0 .2 and 11.0 +/- 0.1, respectively. These affinity values were similar to those obtained 5-HT4 receptors in isolated rat oesophagus (9.0 +/- 0.4, 9.3 +/- 0.1 and 10.6 +/- 0.1, respectively). Despite these operat ional similarities between 5-HT4 receptors in guinea-pig colon and rat oesophagus, several novel compounds have revealed important differenc es between 5-HT4 receptors in the two tissues. For example, the substi tuted benzoate, RS 23597 {3-(piperidine-1-yl) propyl-4-amino-5-chloro- 2-methoxybenzoate hydrochloride, acted as a partial agonist (intrinsic activity 0.5) in guinea-pig colon with a potency of 7.6 +/- 0.1 (n = 16). In isolated rat oesophagus, however, this compound was a surmount able antagonist (pA(2) = 7.8 +/- 0.1) with no intrinsic activity. In c ontrast, the substituted naphthalimide (S)RS 56532 {(S)-6-amino-5-chlo ro-2-(1-azabicyclo[2, 2, 2]octan-3-yl)2,3-dihydro-1H-benz[de] isoquino line-1,3-dione hydrochloride}, was a potent (pEC(50) = 7.9 +/- 0.1), e fficacious partial agonist (intrinsic activity = 0.8) in the rat oesop hagus. However, in guinea-pig colon, it was a surmountable antagonist with an affinity (pK(B)) of 9.4 +/- 0.1. Furthermore, several novel, s elective, 5-HT4 compounds also showed opposing patterns of intrinsic a ctivities similar to those described for RS 23597 and (S)RS 56532. It is concluded that these differences are inconsistent with differences in 5-HT4 receptor reserves, and may suggest that 5-HT4 receptors in th e guinea-pig colon and the rat oesophagus can be operationally disting uished.