Marcinkowska Monika, Kołaczkowski Marcin, Kamiński Krzysztof, Bucki Adam, Pawłowski Maciej, Siwek Agata, Karcz Tadeusz, Starowicz Gabriela, Słoczyńska Karolina, Pękala Elżbieta, Wesołowska Anna, Samochowiec Jerzy, Mierzejewski Paweł, Bienkowski Przemyslaw
Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
Department of Psychiatry, Pomeranian Medical University , 1 Rybacka St., 70-204 Szczecin, Poland.
ACS Chem Neurosci. 2017 Jun 21;8(6):1291-1298. doi: 10.1021/acschemneuro.6b00432. Epub 2017 Mar 1.
Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α-GABA receptors would represent an original approach for the treatment of schizophrenia. This study presents the synthesis and biological evaluation of a series of fluorinated 3-aminomethyl derivatives of 2-phenylimidazo[1,2-a]-pyridine as potential antipsychotic agents. Compound 7 has a high affinity for GABA receptor (K = 27.2 nM), high in vitro metabolic stability, and antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 10 mg/kg). Compound 7 represents a promising point of entry in the course of development of antipsychotic agents with a nondopaminergic mechanism of action.
精神分裂症是一种以行为改变以及解剖学和神经化学异常为特征的精神疾病。在精神分裂症药物研发方面已取得显著进展；然而，作用于单胺能受体以外分子靶点的抗精神病药物尚未研发出来。精神分裂症的一种假说认为，γ-氨基丁酸（GABA）能功能障碍可能在该疾病的病理生理学中起作用。我们最近的研究结果和以往的临床观察表明，通过α-GABA受体调节GABA能系统可能是治疗精神分裂症的一种新方法。本研究介绍了一系列2-苯基咪唑并[1,2-a]吡啶的氟化3-氨基甲基衍生物作为潜在抗精神病药物的合成及生物学评价。化合物7对GABA受体具有高亲和力（K = 27.2 nM），具有较高的体外代谢稳定性，并且在大鼠苯丙胺诱导的运动亢进试验中具有类抗精神病活性（半数有效量 = 10 mg/kg）。化合物7代表了在具有非多巴胺能作用机制的抗精神病药物研发过程中一个有前景的切入点。
