Synthesis and in-vitro pharmacological evaluation of new 5-HT1A receptor ligands containing a benzotriazinone nucleus.

This paper reports the microwave-assisted synthesis and the binding assays on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors of new benzotriazinone derivatives, in order to identify selective ligands for the 5-HT(1A) subtype receptor. Conventional and microwave heating of the reactions were compared. Good yields and short reaction times are the main advantages of our synthetic route. More active compounds were selected and further evaluated for their binding affinities on D(1), D(2) dopaminergic and alpha(1), alpha(2) adrenergic receptors. The 3-(2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one 5 with K(i)= 0.000178 nM was the most active and selective derivative for the 5-HT(1A)receptor with respect to other serotonin receptors and the most selective derivative compared to dopaminergic and adrenergic receptors.

New 5-hydroxytryptamine(1A) receptor ligands containing a norbornene nucleus: synthesis and in vitro pharmacological evaluation.

New arylpiperazine derivatives were prepared to identify highly selective and potent ligands for the 5-hydroxytryptamine 1A (5-HT(1A)) receptor as potential pharmacological tools in studies of central nervous system (CNS) disorders. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain, and arylpiperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in the nanomolar and subnanomolar ranges at 5-HT(1A) and moderate to no affinity for other relevant receptors (5-HT(2A), 5-HT(2C), D(1), D(2), alpha(1), and alpha(2)). The 4-[3-[4-(o-methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione, with K(i) = 0.021 nM, was the most active and selective derivative for the 5-HT(1A) receptor with respect to other serotonin receptors, whereas the most selective derivative for dopaminergic and adrenergic receptors was a CF(3)-substituted arylpiperazine. As a general trend, compounds with a piperazinylpropoxy chain showed a preferential affinity for the 5-HT(1A) receptor, suggesting that the alkyl chain length represents a critical structural feature in determining 5-HT(1A) receptor affinity and selectivity, as confirmed by the molecular modeling invoked for explaining the differential binding affinities of the new arylpiperazines.

Synthesis, beta-adrenergic blocking activity and beta-receptor binding affinities of 1-substituted-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalates.

The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (5) and 1-tert-butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (6) were synthesized from thymol (1), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 microg/kg, i.v.) and 6 (50 microg/kg, i.v.) antagonized isoprenaline (2 microg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 microg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro beta1- and beta2-adrenergic receptor binding assay using turkey erythrocyte membrane (beta1) and lung homogenate of rats (beta2). Both 5 and 6 showed beta-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one beta-adrenergic receptor. These results suggest that both the compounds possess non-selective beta-adrenergic blocking activity, with the tert-butyl derivative 6 being more active than the isopropyl derivative 5.