350 rub
Journal №8 for 2011 г.
Article in number:
Directed search of substances with kappa-opioid agonist activity among heterocyclic systems derivatives
Keywords: kappa-opioid receptors U-50 488 butorphanol norBNI benzimidazole
Authors:
A.A. Spasov, O.J. Grechko, P.M. Vasiljev, V.A. Anisimova
Abstract:
As a result of screen testing in vitro functional assays in rabbit platelet cells exclusively expressed kappa-opioid receptors using the technique of low angle light scattering (Laser particle analyzer LaSca Lumex) it has been revealed that condensed imidazo[1,2-]-benzimidazole derivatives are a perspective class for search of substances with kappa-opioid agonist activity. The greatest degree of kappa-opioid agonism has been achieved in 2,9-di-substituded imidazo[1,2-]-benzimidazole. The importance of substituent at nitrogen atom in the 9-position and also the structure of radical in the 2-position of the heterocyclic core for kappa-agonistic activity has been demonstrated. It has been shown that the presence of a phenyl ring in the С2 position of the heterocyclic core is necessary for kappa-opioid receptor agonism (there is loss of potency when the phenyl fragment of compounds is eliminated). Thus substitution of phenyl ring with halogen atom, especially fluorine, can additionally contribute to kappa-agonist activity and increase efficiency of condensed imidazo[1,2-]-benzimidazole derivatives. Also introduction of the pyrrolidine substituent into dialkylaminoethyl radical in the 9-position leads to significant enhance of kappa-opioid agonist activity of tested compounds. The key pharmacophore elements for kappa-agonist properties of imidazo[1,2-]-benzimidazole derivatives are: hetero aromatic core, containing guanidine fragment, thus a piperidine nitrogen atom in the 1-position is in protonated form; hydrophobic (halogenphenyl) radical at С2-atom of tricycle; aminoethyl-substituent at N9-atom of heterocyclic core, containing as an amine component hydrogenated nitrogen-containing cycles, which nitrogen atom also exists in protonated form, thus the pyrrolidine cycle is optimal for kappa-agonistic activity of presented substances. The most effective 9-dialkylaminoethyl-2-halogenophenylimidazo[1,2-α]-benzimidazoles compounds RU-1203, RU-1204, RU-1205 caused dose-depended norBNI-reversible platelet activation and were approximately 4-fold more potent than the reference kappa-opioid agonists U50,488H and butorphanol. The results allow to consider perspective the further studying of substances RU-1203, RU-1204 and RU-1205 as structurally novel kappa-opioid receptor ligands and suggest the possibility of future efforts to develop such compounds as therapeutic agents for humans without adverse influence on the respiratory center and drug dependence.
Pages: 52-56
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