Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists

Abstract

A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid esters and amides containing a basic azacyclo- or azabicycloalkyl moiety has been synthesized and evaluated for 5-HT3 antagonistic activity in a radioligand binding assay ([3H]ICS 205930) and in the 5-HT-induced von Bezold-Jarisch reflex in the rat. It was found that endo-substituted azabicycloalkyl derivatives (e.g. 7a, 12a, 12b) were much more active than the corresponding exo analogues (e.g. 7b, 12h, 12i) or azacycloalkyl compounds. Amidic derivatives 12a, 12b, 12c, 12e, 13b, and 13c proved to be about 10 times more active than the corresponding ester derivatives 7a, 11a, 7c, 7d, 8a, and 8b. In particular, compound 12a (DA 6215) showed a Ki = 3.8 nM in the binding test and an ED50 = 1 nM/kg iv in the von Bezold-Jarisch reflex assay, an activity comparable to that of the reference compound 2 (ICS 205930, Ki = 2 nM, ED50 = 2.1 nM/kg). IR spectroscopy studies in the solid state and in CHCl3 solution revealed the existence of an intramolecular hydrogen bond in 13b, taken as a model compound for this class of substances. A molecular modeling study showed that 12a, in its internal hydrogen-bound conformation, well matches a recently proposed pharmacophoric model for 5-HT3 antagonist activity.

The 5‐HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP‐dependent protein kinase

“…An alternative was to use the azabicycloalkyl benzimidazolone derivative, DAU 6285 (Turconi et al, 1990), a drug that we found to inhibit cyclic AMP production induced by specific 5-HT4 receptor agonists in cultured colliculi neurones (Dumuis et al, 1992). At a concentration of 10 gM, DAU 6285 had no effect by its own on K+ currents of colliculi …”

“…BIMU 8 and more classically renzapride (Turconi et al, 1990) also display 5-HT3 antagonistic activity in receptor binding assays and physiological tests. However, it seems unlikely that this property of BIMU 8 and renzapride accounted for the drug effects observed here on the K+ current in colliculi neurones since another potent and specific 5-HT3 antagonist, ondansetron, did not alter the current.…”

Effects of DAU 6215, a novel 5‐hydroxytryptamine3 (5‐HT3) antagonist on electrophysiological properties of the rat hippocampus

“…In the last few years a novel class of 5-hydroxytryptamine3 (5-HT3) receptor antagonist has been synthesized (Turconi et al, 1990) and the potency and selectivity of these new molecules have been tested in isolated preparations and in vivo models. Among these compounds, DAU 6215 (endo-N- (8-methyl-8-azabicyclo-[3.2.…”

“…Among these compounds, DAU 6215 (endo-N- (8-methyl-8-azabicyclo-[3.2. 1]-octo-3-yl)-2,3-dihydro-2-oxo-lHbenzimidazole-l-carboxamide hydrochloride), a benzimidazolone derivative, exhibits a high affinity for the [3H]-ICS binding site in rat brain tissue, and it is equipotent with ICS 205-930 in inhibiting 5-HT-induced bradycardia in rats (Turconi et al, 1990;1991a). DAU 6215 was also found to be a weak, partial agonist at the 5-HT4 receptor, as demonstrated by the ability of this compound to stimulate adenosine 3':5'-cyclic monophosphate (cyclic AMP) production in colliculi neurones in cultures (Dumuis et al, 1991).…”

Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

“…Examples were the best suitable diastereomer did not exceed the activity of the aminopiperidine derivative include analogues of the analgesic fentanyl 12 (decahydroquinoline type [108], isoquinuclidine type [101,109], tropane type [110], granatane type [111] and norcamphidine type [94]), of the neuroleptic Pipamperone 1 (azabicyclohexane type [64]) or of the analgesic piritramide 2 (azabicyclohexane type [72]). A clear improvement of activity, however, was performed with the substances 102 (analogue of bamipine 6 and 15 times more active [76,83]), 103 (analogue of Clebopride 9 and 30 times more active [26]) and 104a (300 times more active than the analogous aminopiperidine derivative [27]) (Fig. 14).…”