Skip to main content
SpringerLink
Log in

Comparison of 5-HT4 receptors in guinea-pig colon and rat oesophagus: effects of novel agonists and antagonists

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

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-carboxylat}, RS 39604 {1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)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 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adham N, Gerald C, Schechter LE, Weinshank RL Branchek TA (1994) [3H]5-HT labels the high affinity state of the cloned rat 5-HT4 receptor. Third IUPHAR satellite meeting on serotonin. Abstract number 55

  • Adham N, Gerald C, Vaysse PJJ, Weinshank RL, Branchek A (1995) Characterization of the functional responses mediated by two splice variants of the cloned rat 5-HT4 receptor in heterologus expression systems. Br J Pharmacol 114:158P

  • Arunlakshana O, Schild NO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58

    Google Scholar 

  • Baxter GS, Craig DA, Clarke DE (1991) 5-Hydroxytryptamine4 receptors mediate relaxation of the rat oesophageal tunica muscularis mucosae. Naunyn-Schmiedeberg's Arch Pharmacol 343:439–446

    Google Scholar 

  • Bockaert J, Sebben M, Dumuis A (1990) Pharmacological characterization of 5-HT4 receptors positively coupled to adenylate cyclase in adult guinea-pig hippocampal membranes: effects of substituted benzamide derivatives. Mol Pharmacol 37:408–411

    Google Scholar 

  • Briejer MR, Akkermans LMA, Schuurkes JAJ (1995) Gastrointestinal prokinetic benzarnides: the pharmacology underlying stimulation of motility. Pharmacol Rev 47:631–651

    Google Scholar 

  • Cheng Y-C, Prusoff WH (1973) Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Google Scholar 

  • Clark RD, Weinhardt KK, Berger J, Lee CH, Leung E, Wong EHF, Smith WL, Eglen RM (1993) N-(quinuclidin-3-yl)-1,8-naphthalimides with 5-HT3 receptor antagonist and 5-HT4 receptor agonist properties. BioOrg Med Chem Lett 3:1375–1378

    Google Scholar 

  • Clark RD, Jahangir A, Langston JA, Weinhardt KK, Miller AB, Leung E, Eglen RM (1994a) Ketones related to the benzoate 5-HT4 receptor antagonist RS-23597 are high affinity partial agonists. BioOrg Med Chem Lett 4:2477–2480

    Google Scholar 

  • Clark RD, Jahangir A, Langston JA, Weinhardt KK, Miller AB, Leung E, Bonhaus DW, Wong EHF, Eglen RM (1994b) Synthesis and preliminary pharmacological evaluation of 2-Benzyloxy substituted aryl ketones as 5-HT4 receptor antagonists. BioOrg Med Chem Lett 4:2481–2484

    Google Scholar 

  • Clark RD, Muchowski JM, Weinhardt KK, Dillon MP, Lee CH, Bley KR, Bonhaus DW, Wong EHF, Eglen RM (1995) N-(quinuclidin-3-y1)-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide: a high affinity 5-HT3 receptor partial agonist. BioOrg Med Chem Lett 5:1853–1856

    Google Scholar 

  • Craig DA, Clarke DE (1990) Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in guinea-pig ileum with properties similar to the 5-hydroxytryptamine4 receptor. J Pharmacol Exp Ther 252:1378–1385

    Google Scholar 

  • Craig DA, Eglen RM, Walsh LKM, Perkins LA, Whiting RL, Clarke DE (1990) 5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine desensitization as discriminative tools for the 5-HT3 and putative 5-HT4 receptors in guinea-pig ileum. Naunyn-Schmiedeberg's Arch Pharmacol 342:9–16

    Google Scholar 

  • Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J (1988) A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol 34:880–887

    Google Scholar 

  • Dumuis A, Sebben M, Bockaert J (1989) The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn-Schmiedeberg's Arch Pharmacol: 340:403–410

    Google Scholar 

  • Eglen RM, Swank SR, Walsh LKM, Whiting RL (1990) Characterization of 5-HT3 and ‘atypical’ 5-HT receptors mediating guinea-pig ileal contractions in vitro. Br J Pharmacol 101:513–520

    Google Scholar 

  • Eglen RM, Perkins LA, Walsh LKM, Whiting RL (1992) Agonist action of indole derivatives at 5-HT1-likes 5-HT3, and 5HT4 receptors in vitro. J Anton Pharmacol 12:321–333

    Google Scholar 

  • Eglen RM, Alvarez R, Johnson LG, Leung E, Wong EH (1993a) The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors. Br J Pharmacol 108:376–382

    Google Scholar 

  • Eglen RM, Bley K, Bonhaus DW, Clark RD, Hegde SS, Johnson LG, Leung E, Whiting RL (1993b) RS-23597–190: a potent and selective 5-HT4 receptor antagonist. Br J Pharmacol 110:119–126

    Google Scholar 

  • Eglen RM, Bonhaus DW, Clark RD, Johnson LG, Lee C-H, Leung E, Smith WL, Wong EHF, Whiting RL (1994) (R) and (S) RS 56532: Mixed 5-HT3 and 5-HT4 receptor ligands with opposing enantiomeric selectivity. Neuropharmacology 33:515–526

    Google Scholar 

  • Eglen RM, Bonhaus DW, Clark RD, Johnson LG, Leung E (1995a) RS-17017, RS-67333 and RS-67506: Potent and selective 5-HT4 receptor partial agonists in vitro and in vivo. Br J Pharmacol 114:159P

  • Eglen RM, Bonhaus DW, Johnson LG, Leung E, Clark RD (1995b) Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo. Br J Pharmacol 115:1387–1392

    Google Scholar 

  • Elswood CJ, Bunce KT, Humphrey PPA (191) Identification of 5-HT4 receptors in guinea-pig ascending colon. Eur J Pharmacol 196:149–155

  • Ford APDW, Clarke DE (1993) The 5-HT4 receptor. Med Res Rev 13:633–662

    Google Scholar 

  • Ford APDW, Baxter GS, Eglen RM, Clarke DE (1992) 5-Hydroxytryptamine stimulates cyclic AMP formation in the tunica muscularis mucosae of the rat oesophagus via 5-HT4 receptors. Eur J Pharmacol 211:117–120

    Google Scholar 

  • Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blashko H, Muscholl E (eds) Handbook of experimental pharmacology, Catecholamines, vol 33. Springer, New York, pp 283–335

    Google Scholar 

  • Gale JD, Grossman CJ, Whitehead JWF, Oxford AW, Bunce KT, Humphrey PPA (1994) GR113808: a novel selective antagonist with high affinity at the 5-HT4 receptor. Br J Pharmacol 111:332–338

    Google Scholar 

  • Gerald C, Adham N, Kao HT, Olsen MA, Laz TM, Schechter LE, Bard JA, Vaysse PJJ, Hartig PR, Branchek TA, Weinshank RL (1995) The 5-HT4 receptor — molecular cloning and pharmacological characterization of two splice variants. EMBO J 14:2806–2815

    CAS  PubMed  Google Scholar 

  • Gullikson GW, Virina MA, Loeffler RF, Yang DC, Goldstin B, Wang S-X, Moummi C, Flynn DL, Zabrowski DL (1993) SC49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism. J Pharmacol Exp Ther 264:240–248

    Google Scholar 

  • Hegde SS, Bonhaus DW, Johnson LG, Leung E, Clark RD, Eglen RM (1995) RS 39604: A potent, selective and orally active 5-HT4 receptor antagonist. Br J Pharmacol 115:1087–1095

    Google Scholar 

  • Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA (1994) VII. International Union of Pharmacology Classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203

    Google Scholar 

  • Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ (1990) A 5-hydroxytryptamine receptor in human atrium. Br J Pharmacol 100:879–885

    CAS  PubMed  Google Scholar 

  • Kenakin T (1995a) Agonist-receptor efficacy. I: Mechanisms of efficacy and receptor promiscuity. Trends Pharmacol Sci 16:188–192

    Google Scholar 

  • Kenakin T (1995b) Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol Sci 16:232–238

    Google Scholar 

  • Kilbinger H, Gebauer A, Haas J, Ladinsky H, Rizzi CA (1995) Benzimidazolones and renzapride facilitate acetylcholine release from guinea-pig myenteric plexus via 5-HT4 receptors. Naunyn-Schmiedeberg's Arch Pharmacol 351:229–236

    Google Scholar 

  • Leung E, Michelson S, Villarubia C, Perkins LA, Eglen RM (1992) Analysis of concentration-response relationships by seemingly unrelated nonlinear regression (SUNR) technique. J Pharmacol Methods 28:209–216

    Google Scholar 

  • Leung E, Pulido-Rios MT, Wong EHF and Eglen RM (1995) Characterization of 5-hydroxytryptamine (5-HT)4 receptors in guinea pig distal colon. FASEB J 9: Abstract number 5538, A954

    Google Scholar 

  • McLean PG, Coupar IM (1995) 5-HT4 receptor antagonist affinities of SB 204070, SB 205008, and SB 203186 in the human colon, rat oesophagus, and guinea-pig ileum peristaltic reflex. Naunyn-Schmiedeberg's Arch Pharmacol 252:132–140

    Google Scholar 

  • McLean PG, Coupar IM, Molenaar P (1995) A comparative study of 5-HT4 receptors in human colon, rat oesophagus and rat ileum. Br J Pharmacol 115:47–56

    Google Scholar 

  • Medhurst AD, Kaumann AJ (1993) Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium. Br J Pharmacol 110:1023–1030

    Google Scholar 

  • Milligan G (1993) Mechanisms of multifunctional signalling by G-protein-linked receptors. Trends Pharmacol Sci 14:239–244

    Google Scholar 

  • Parker RB, Wand DR (1971) Pharmacological estimation of drug-receptor dissociation constants. Statistical evaluation. I. Agonists. J Pharmacol Exp Ther 177:1–12

    Google Scholar 

  • Reynolds GP, Mason SL, Meldrum A, De Keczer S, Parnes H, Eglen RM, Wong EHF (1995) 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerate diseases. Br J Pharmacol 114:993–998

    Google Scholar 

  • Rizzi CA, Coccini T, Onori L, Manzo L, Tonini M (1992) Benzimidazolone derivatives: A new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea-pig ileum. J Pharmacol Exp Ther 261:412–419

    Google Scholar 

  • Sanger GJ (1987) Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924. Br J Pharmacol 91:77–87

    Google Scholar 

  • Tam FS-F, Hillier K, Bunce KT, Grossman C (1995) Differences in response to 5-HT4 receptor agonists and antagonists of the 5-HT4-like receptor in human colon circular smooth muscle. Br J Pharmacol 115:172–176

    Google Scholar 

  • Waikar MV, Hegde SS, Ford APDW, Clarke DE (1993) Pharmacological analyses of endo-6-methoxy-8-methyl-8-azabicyclo [3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H-benzimidazole-l-carboxylate hydrochloride (DAU 6285) at the 5-hydroxytryptamine4 receptor in the tunica muscularis mucosae of rat oesophagus and ileum of guinea pig: role of endogenous 5-hydroxytryptamine. J Pharmacol Exp Ther 264:654–661

    Google Scholar 

  • Wardle KA, Sanger GJ (1993) The guinea-pig distal colon — a sensitive preparation for the investigation of 5-HT4 receptor-mediated contractions. Br J Pharmacol 110:1593–1599

    Google Scholar 

  • Wardle KA, Ellis ES, Baxter GS, Kennett GA, Gaster LM, Sanger GJ (1994) The effects of SB 204070, a highly potent and selective 5-HT4 receptor antagonist, on guinea-pig distal colon. Br J Pharmacol 112:789–794

    Google Scholar 

  • Wong EHF, Hsu S, Leung E, Berger J, Clark R, Bonhaus DW, Eglen RM (1995) Labelling 5-HT4 receptors with a novel agonist radioligand, [3H]RS 57639-190. J Neurochem 65:S26B

  • Zeitung KD, Perkins LA, Hsu SAO, Bonhaus DW, Eglen RM, Wong EHF, Leung E (1994) Comparison of GR 113808 and SB 204070 at 5-HT4 receptors in vitro. FASEB J 8: Abstract no. 533, A92

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pharmacology, R2-101, Neurobiology Unit, Roche Bioscience, 3401 Hillview Avenue, 94304, Palo Alto, CA, USA

    E. Leung, M. T. Pulido-Rios, D. W. Bonhaus, L. A. Perkins, K. D. Zeitung, S. A. O. Hsu, E. H. F. Wong & R. M. Eglen

  2. Medicinal Chemistry Unit, Neurobiology Unit, Roche Bioscience, 3401 Hillview Avenue, 94304, Palo Alto, CA, USA

    R. D. Clark

Authors
  1. E. Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. T. Pulido-Rios
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. W. Bonhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. A. Perkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. D. Zeitung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. A. O. Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. D. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E. H. F. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. M. Eglen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leung, E., Pulido-Rios, M.T., Bonhaus, D.W. et al. Comparison of 5-HT4 receptors in guinea-pig colon and rat oesophagus: effects of novel agonists and antagonists. Naunyn-Schmiedeberg's Arch Pharmacol 354, 145–156 (1996). https://doi.org/10.1007/BF00178714

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00178714

Key words

Search

Navigation