Summary
Recent experimental evidence indicates that central 5-HT4 receptors which are positively coupled to adenylate cyclase, are stimulated by a family of 2-methoxy-4-amino-5-chloro substituted benzamide derivatives. These compounds are also potent stimulants of the gastro-intestinal motility. In this study the ability of three azabicycloalkyl benzimidazolone derivatives, BIMU 1, BIMU 8, and DAU 6215 (structural formulas are given in the text), to stimulate cAMP formation in colliculi neurons in primary culture have been tested. Two of the compounds, BIMU 1 and BIMU 8, which show prokinetic activity in various animal models, were also good agonists at the 5-HT4 receptors, whereas DAU 6215, a drug devoid of prokinetic activity, was only a weak, partial agonist at 5-HT4 receptors.
The rank order of their potencies as compared with those of 5-HT and cisapride was as follows: BIMU 8 = cisapride > 5-HT > BIMU 1 > DAU 6215. The efficacies of BIMU 8 and cisapride were comparable (133 ± 9% and 124 ± 8% of the maximal 5-HT efficacy, respectively), whereas BIMU 1 and DAU 6215 elicited, respectively, only 72 ± 11 % and 16 ± 4% of the maximal 5-HT effect. The activities of the azabicycloalkyl benzimidazolone derivatives and 5-HT on cAMP formation were not additive and ICS 205–930 antagonized the stimulatory effect of these compounds with low potency (pKi = 6.1–6.4), further strengthening the notion of interaction with 5-HT4 receptors. In addition, cross desensitization between the effects of 5-HT and the azabicycloalkyl benzimidazolones on adenylate cyclase was noted, another argument in favor of an interaction of these drugs on 5-HT4 receptors.
Similar content being viewed by others
References
Bockaert J, Sebben M, Dumuis A (1990) Pharmacological characterization of 5-HT4 receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. Mol Pharmacol 37:408–411
Borsini F, Templeton D, Turconi M, Nicola M, Schiantarelli P, Donetti A (1990) Anxiolytic effects of a new structural class of 5-HT3 antagonists (Abstract). 3rd International Meeting of the European Behavioral Pharmacology Society, 27–30 June, Noordwijkerhout, The Netherlands
Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 25:563–576
Buchheit KH, Engel G, Mutschler E, Richardson BP (1985) Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea pig ileum. Evidence for two distinct release mechanisms. NaunynSchmiedeberg's Arch Pharmacol 329:36–41
Clarke DE, Craig DA, Fozard JR (1989) The 5-HT4 receptor: naughty, but nice. Trends Pharmacol Sci 10:385–386
Craig DA, Clarke DE (1989) 5-Hydroxytryptamine and cholinergic mechanisms in guinea pig ileum. Br J Pharmacol 96:247P
Craig DA, Clarke DE (1990) Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in guinea pig ileum with properties similar to the 5-hydroxytryptamine-4 receptor. J Pharmacol Exp Ther 252:1378–1386
Craig DA, Eglen RM, Walsh LKM, Perkins LA, Whiting RL, Clarke DE (1990) 5-Methoxytryptamine and 2-methyl-5hydroxytryptamine induced 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
Dumuis A, Bouhelal R, Sebben M, Bockaert J (1988a) A 5-HT receptor in the central nervous system positively coupled with adenylate cyclase is antagonized by ICS 205–930. Fur J Pharmacol 146:187–188
Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J (1988b) A non classical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol 34:880–887
Dumuis A, Sebben M, Bockaert J (1989a) BRL 24924, a potent agonist at a non classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons. Eur J Pharmacol 162:381–384
Dumuis A, Sebben M, Bockaert J (1989b) The gastrointestinal prokinetic benzamine 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
Fozard JR (1990) Agonists and antagonists of 5-HT3 receptors. In: Saxena PR, Wallis DI, Wouters W, Bevan P (eds) Cardiovascular pharmacology of 5-hydroxytryptamine. Kluwer, Dordrecht, pp 101–115
Giraldo E, Monti L, Turconi M, Nicola M, Donetti A, Ladinsky H (1989) Binding affinities of a novel class of serotonin 5-HT3 receptor antagonists (Abstract). International symposium of serotonin from cell biology to pharmacology and therapeutics, Florence, Italy, 69 P
Kilpatrick GJ, Jones BJ, Tyers MB (1987) Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 330:746–748
Peroutka SJ (1988) 5-Hydroxytryptamine receptor subtypes: molecular, biochemical and physiological characterization. TINS 11:496–500
Richardson BP, Engel G, Donatsch P, Stadler PA (1985) Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature (London) 316:126–131
Richardson BP, Buchheit KH (1988) The pharmacology, distribution and function of 5-HT3 receptors. In: Osborne NN, Hamon M (eds) Neuronal serotonin. Chichester, pp 465–504
Rizzi CA, Onori L, Sanguini AM, Coccini T, Tonini M (1990) Facilitation of cholinergic transmission and peristalsis induced by a novel class of benzimidazolone derivatives in the guinea-pig small intestine (Abstract). Second IUPHAR satellite meeting on serotonin, 152P
Sanger GJ (1985) Three different ways in which 5-hydroxytryptamine can affect cholinergic activity in guinea pig isolated ileum. J Pharm Pharmacol 37:584–586
Sanger GJ (1987a) 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
Sanger GJ (1987b) Activation of a myenteric 5-hydroxytryptamine-like receptor by metoclopramide. J Pharm Pharmacol 39: 449–453
Schiantarelli P, Bockaert J, Cesana R, Donetti A, Dumuis A, Giraldo E, Ladinsky H, Monferini E, Rizzi C, Sagrada A, Shiavone E (1990) The prokinetic properties of new benzimidazolone derivatives are related to 5-HT4 antagonism (Abstract). XXV meeting of Italia Society of Pharmacology, 14–18 October, Taormina, Italy
Schiavone A, Cesana R, Micheletti R, Rizzi CA, Turconi M, Nicola M, Schiantarelli P, Donetti A (1990) Prokinetic activity of a novel non benzamidec compound (Abstract). Second IUPHAR satellite meeting on serotonin: 153P
Schmidt M, Imbs JL, Schwartz J (1981) The vascular dopamine receptor: a review. J Pharmacol (Paris) 4:355–382
Schuurkes JAJ, Van Nueten JM, Van Deale PGH, Reyntjens AJ, Janssen PAJ (1985) Motor stimulating properties of cisapride on isolated gastrointestinal preparations on the guinea pig. J Pharmacol Exp Ther 234:775–783
Schuurkes JAJ, Megers AAHP, Niemegeers CJE, Leysen JE, Van Nueten JM (1987) A comparative study of the cholinergic vs the anti-dopaminergic properties of benzamides with gastrointestinal prokinetic activity. In: Szurzewki J (ed) Cellular physiology and clinical studies of gastrointestinal smooth muscle. Elsevier/North Holland, Amsterdam, pp 231–247
Tonini M, Rizzi CA, Manzo L, Onori L (1991) Novel enteric 5-HT4 receptors and gastointestinal prokinetic action. Pharmacol Res (in press)
Turconi M, Nicola M, Gil Quintero M, Giraldo E, Micheletti R, Rizzi CA, Donetti A (1990 a) Azabicycloalkyl benzimidazolone derivatives: a novel class of 5-HT3 receptor antagonists. 199th ACS National Meeting, MEDI 103, Boston, 22–27 April
Turconi M, Nicola M, Gill Quintero M, Maiocchi L, Micheletti R, Giraldo E, Donetti A (1990b) Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivative as highly potent 5-HT3 receptor antagonists. J Med Chem 33:2101–2108
Weiss S, Sebben M, Garcia-Sainz JA, Bockaert J (1985) D2-dopamine receptor-mediated inhibition of cyclic AMP formation in striatal neurons in primary culture. Mol Pharmacol 27:595–599
Weiss S, Pin JP, Sebben M, Kemp DE, Sladeczek F, Gabrion J, Bockaert J (1986) Synaptogenesis of cultured striatal neurons in serum-free medium: a morphological and biochemical study. Proc Natl Acad Sci USA 83:2238–2242
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dumuis, A., Sebben, M., Monferini, E. et al. Azabicycloalkyl benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in braina. Naunyn-Schmiedeberg's Arch Pharmacol 343, 245–251 (1991). https://doi.org/10.1007/BF00251122
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00251122