ISSN:
1432-1912
Keywords:
Key words 5-HT4 receptors
;
Guinea-pig distal colon
;
Rat oesophagus
;
GR 113808
;
SB 204070
;
(S)RS 56532
;
RS 23597
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 5-HT4 receptors in isolated distal colon myenteric plexus of guinea-pig, mediating contraction of longitudinal smooth muscle, have been further characterized by selective agonists and antagonists. The indole agonists, 5-HT and 5-methoxytryptamine (5-MeOT), were full agonists (relative to 5-HT) with potency values (pEC50) of 8.0±0.1 (n=50) and 7.8±0.1(n=12), respectively. 5-HT4 receptor agonists of other structural classes, including benzimidazolones (BIMU 1 and BIMU 8), and benzamides ((S)-zacopride, (R)-zacopride, renzapride, SC 49518) were partial agonists with intrinsic activities less than that of 5-HT. In general, the potencies for these compounds at 5-HT4 receptors in guinea-pig colon were similar to the potencies seen in the rat isolated oesophagus, where 5-HT4 receptors mediate relaxation. GR 113808 {[1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl1-methyl-1H-indole-3-carboxylate }, RS 39604 {1-[4-amino-5-chloro-2-(3, 5-dimethoxybenzyl-oxy)phenyl]-3-[1-[2-[(methylsulfonyl)amino] ethyl]-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 pA2 values of 9.1±0.1, 9.0±0.2 and 11.0±0.1, respectively. These affinity values were similar to those obtained at 5-HT4 receptors in isolated rat oesophagus (9.0±0.4, 9.3±0.1 and 10.6±0.1, respectively). Despite these operational similarities between 5-HT4 receptors in guinea-pig colon and rat oesophagus, several novel compounds have revealed important differences between 5-HT4 receptors in the two tissues. For example, the substituted 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 surmountable antagonist (pA2=7.8±0.1) with no intrinsic activity. In contrast, the substituted naphthalimide (S)RS 56532 {(S)-6-amino-5-chloro-2-(1-azabicyclo[2, 2, 2]octan-3-yl)2,3-dihydro-1H-benz[de] isoquinoline-1,3-dione hydrochloride}, was a potent (pEC50=7.9±0.1), efficacious partial agonist (intrinsic activity = 0.8) in the rat oesophagus. However, in guinea-pig colon, it was a surmountable antagonist with an affinity (pKB) of 9.4±0.1. Furthermore, several novel, selective, 5-HT4 compounds also showed opposing patterns of intrinsic activities 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 the guinea-pig colon and the rat oesophagus can be operationally distinguished.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00178714
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