title: Physico-chemical characterization of a novel group of dopamine D(3)/D(2) receptor ligands, potential atypical antipsychotic agents.
abstract: The fundamental physico-chemical properties such as ionization and lipophilicity of twelve alkyl-aryl-piperidine and aryl-piperazine derivatives have been determined. Compounds are members of a recently identified, new class of potent dopamine D(3)/D(2) receptor ligands as potential atypical antipsychotic agents and were used in the development of a promising drug candidate (RGH-188) being present currently in clinical phase II investigations. The ionization constant (pK(a)) and the partition coefficient in octanol/water (logP(oct)) and cyclohexane/water systems (logP(ch)) were measured by validated analytical methods. Based on the highly precise physico-chemical data the structure-property relationships (SPR) were studied. The effect of the polar and apolar heteroatoms as well as polar and apolar surface areas on the partition in the two solvent systems was investigated by linear regression and multivariate linear regression analyses. Brain/blood concentration ratios (BB values) as a function of time were determined by HPLC analyses on plasma and brain homogenates of Wistar rats. A linear relationship has been found between DeltalogP values (logP(oct)-logP(ch)) and experimental logBB values, verifying that physico-chemical data can predict pharmacokinetic behaviour.
authors.affiliation: Analytical Laboratory, Formulation Development, Gedeon Richter Plc., H-1103 Gyömroi u. 19-21. Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Deák
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Novák
authors.forename: Margit
authors.initials: M
authors.lastname: Kapás
authors.forename: Mónika
authors.initials: M
authors.lastname: Vastag
authors.forename: Károly
authors.initials: K
authors.lastname: Tihanyi
authors.forename: Béla
authors.initials: B
authors.lastname: Noszál
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000502:physiology*; D055598:Chemical Phenomena; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003510:Cyclohexanes / Q000737:chemistry; D008024:Ligands; D016014:Linear Models; D015394:Molecular Structure; D015999:Multivariate Analysis; D000442:Octanols / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D014150:Antipsychotic Agents; D003510:Cyclohexanes; D008024:Ligands; D000442:Octanols; D010879:Piperazines; D010880:Piperidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D014867:Water; C506365:Cyclohexane