A series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives were prepared in order to determine the necessary structural requirements for good affinity for 5-HT1A receptors and high selectivity versus other receptors. Modifications of the extracyclic amino substituents, the length of the alkyl side chains, and their substituents were explored. The best compounds (9g, 9k, 15b, 15d) possess imido or sulfonamido functional groups with a preferential length of four methylenes for the side chain. After resolution, the dextrorotatory enantiomers showed better affinity and selectivity for 5-HT1A receptors. These compounds have been proven to be full agonists. 9g and its enantiomers showed anxiolytic activity in vivo in various comportemental models. The compound (+)-9g is currently under clinical investigation.
A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.
In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.
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