Synthesis, structure and affinity for receptors of the central nervous system of the aryl(hetaryl) piperazine derivatives

Projektinformationen

ID Finanzhilfevereinbarung: INTAS-94-0839

Projekt abgeschlossen

Startdatum 1 Juni 1995

Enddatum 31 Mai 1998

Finanziert unter

• International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Gesamtkosten

Keine Daten

EU-Beitrag

€ 64 000,00

Koordiniert durch

Consiglio Nazionale delle Ricerche (CNR)
Italy

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Verwertbare Ergebnisse

Synthesis, structure and affinity for receptors of the central nervous system the aryl (hetaryl) piperazine derivatives

Buspirone and its analogues (N-arylpiperazinylalkylphthalimides and - naphthalimides, succinimido- and glutarimidobutyl-2-(pyrimidinyl) piperazines, peiperazinylquinazolines and phenylpiperazinylbutylheterocycles) have been synthesised. The conformational mobility of buspirone and its analogues in solution and effects of the electronic transition have been studied using NMR-spectroscopy methods. It has been shown that an extension of methylene bridge from n=1 to n=5 leads to a decrease of the dihedral angle between planes of N-(2-pyrimidinyl) piperazine and phthalimide (azaspiroalkanedione, succinimide, glutarimide, e.g.) fragments is in range from 90 to 30 . Conclusion on the more extended conformation of naphthalimide derivative as compared with the phthalimidederivatives has been made. The affinity of the obtained compounds for serotonin (5-HT1A), dopamine (D1, D2) and benzodiazepine receptors have been determined by the radioligand method. Psychopharmacological properties of the obtained aryl(hetaryl)piperazines (anxiolytic and anticonvulsant) have been studied. Influence of the aryl substituent structure, of the hydrocarbon spacor length and of so-called imide fragment on the affinity of the obtained compounds for 5-HT1A receptors. Good correlation between affinity for 5-HT1A receptors and anxiolytic activity of arylpiperazinylbutylphthalimides has been found. The crystal and molecular structures of 18 synthesised compounds were established by X-ray diffraction analyses. It was supposed that for ligands, possessing the considerable affinity to 5-HT1A receptors, the distances from N 2 atom to the aromatic ring may ranges from 5.6 up to 6.2 A. Conformational analysis of the compounds showed that the rotation around single bonds in alkyl spacer can lead to a claw-like shape of the molecules. The extended rod-like form hetaryl(aryl) piperazines derivatives, its donor properties which are determined mainly by the N1 atom ppi - orbital and the phenyl ring ppi orbitals and the MEP distribution in the vicinity of the aromatic ring, N1, N2 atoms of piperazine cycle and phthalimide (naphthalimide) fragment should help to understand the recognition of ligands, via intermolecular hydrogen bonds to 5-HT receptor. It is noted that substitution in aryl substituent of phthalimide and naphthalimide derivatives has different influence on their affinity for 5-HT1A receptors. The quantitative structure-affinity relationships to 5-HT1A receptors have been studied. The equation expressed relation Ki value and structure parameters have been obtained.