Marco Turconi

DAU 6285: A novel antagonist at the putative 5-HT4 receptor

The antagonistic properties of DAU 6285, an azabicycloalkyl benzimidazolone derivative, at putative 5-hydroxytryptamine4 (5-HT4) receptors were investigated in in vitro preparations of guinea-pig ileum and human atrium, in comparison to ICS 205-930. DAU 6285 behaved as a competitive antagonist in all the preparations examined. Its affinity (pA2) ranged between 6.50 and 7.12 in the test models considered. The affinity of ICS 205-930 was 2-3 fold lower. At variance with ICS 205-930, DAU 6285 displayed a weak affinity for 5-HT3 receptors (pKi = 6.1, rat cortex; pA2 less than 5, guinea-pig ileum). In the guinea-pig ileum, DAU 6285 (10 microM) did not exert antimuscarinic, antihistaminic, antinicotinic or myolytic activity. Moreover, it did not bind to other 5-HT receptor subtypes, or to adrenergic, dopaminergic, benzodiazepine, nicotine, GABA receptors. DAU 6285 may represent a suitable tool for studies in the field of 5-HT4 receptors.

Pharmacological properties of a novel class of 5-HT3 receptor antagonists

The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.

Anti-secretory and anti-ulcer activities of some new 2-(2-pyridylmethyl-sulfinyl)-benzimidazoles

Abstract A series of substituted sulfinyl benzimidazoles were prepared and tested for gastric anti-secretory activity. Following initial screening, two compounds were tested for anti-ulcer activity. The new compounds showed pharmacological properties different from those of omeprazole 1 , since they proved to be weak anti-secretory agents displaying non-specific anti-ulcer activity. Some structural requirements for optimum activity were elucidated.

The novel 5-HT4 receptor antagonist DAU 6285 antagonizes 5-hydroxytryptamine-induced tachycardia in pigs.

The 5-HT4 receptor antagonist action of DAU 6285 was investigated in vivo in anesthetized pigs. DAU 6285 (0.3-3 mg/kg i.v.) dose dependently antagonized 5-hydroxytryptamine (5-HT)-induced tachycardiac responses. In contrast, the 5-HT3 receptor antagonist, ondansetron (0.3-3 mg/kg i.v.) did not influence the tachycardia induced by 5-HT. These results indicate that DAU 6285 is a potent antagonist of 5-HT4 receptor-mediated responses in vivo.

Synthesis, absolute configuration, conformational analysis and binding affinity properties of enantiomeric forms of DAU 5750, a novel M1–M3 muscarinic receptor antagonist

Both the enantiomeric forms of DAU 5750, a novel muscarinic receptor antagonist, have been synthesized in order to assess the relevance of configurational/conformational features for high affinity binding to muscarinic receptor subtypes. The attribution of absolute stereochemistry and conformational analysis by means of molecular modelling and NMR techniques are also reported.

The role of electronic and conformational properties in the activity of 5-HT3 receptor antagonists

Abstract The conformational and electronic properties of 11 5-HT 3 receptor antagonists, were investigated to rationalize their biological activity. All compounds fulfill the previously reported geometrical requirements for the pharmacophore, although they show a wide spectrum of activities. Quantitative structure-activity relationships (QSAR) models were searched using the cross-validated partial least squares technique. The results of the QSAR analysis show that a unique model can rationalize both the in vitro (affinity, K d ) and the in vivo (50% inhibitory dose, ID 50 ) activities. This model includes the value of the molecular electrostatic potential minimum above the aromatic fragment, used as an index of the π-electron density, as well as the relative population of the anti-periplanar (app, the “active”) conformation. Two other models were also obtained that include electrophilic superdelocalizability indexes. Although these models give a more satisfactory value of the cross-validated correlation coefficient ( R 2 cv ), they represent two different models for K d and ID 50 which is in contrast with the experimental evidence that a correlation exists between these two activities. It is concluded that the use of electronic and conformational properties in addition to the geometrical characteristics may better describe and predict the activity of 5-HT 3 receptor antagonists, than the use of geometrical characteristics alone.