O'Donovan Daniel H, Muguruza Carolina, Callado Luis F, Rozas Isabel
School of Chemistry, TBSI, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
Department of Pharmacology, University of the Basque Country UPV/EHU, and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain.
Eur J Med Chem. 2014 Jul 23;82:242-54. doi: 10.1016/j.ejmech.2014.05.057. Epub 2014 May 27.
Depression has been linked to a selective increase in the high affinity conformation of the α2-adrenergic autoreceptors (α2-ARs) in the human brain as well as to an overexpression of α2-ARs in the hippocampus and cerebral cortex. Thus, the development of novel α2-AR antagonists represents an attractive source of new antidepressants. This paper describes the design, synthesis and pharmacological evaluation of 30 new guanidinium and 2-iminoimidazolidinium as potential α2-AR antagonists. In order to design this new series of α2-AR antagonists, a pharmacophore model was developed using the GALAHAD software. This study suggested that increased substitution in the space surrounding the cationic guanidine moiety might lead selectively to antagonist activity. Following the preparation of compounds incorporating this feature and competitive radioligand binding, [(35)S]GTPγS functional assays revealed that this structural modification affords exclusively α2-AR antagonists, in contrast with the analogous unsubstituted compounds in which a mixture of antagonist/agonist activities was previously observed.
抑郁症与人脑α2 - 肾上腺素能自身受体（α2 - ARs）高亲和力构象的选择性增加以及海马体和大脑皮层中α2 - ARs的过度表达有关。因此，新型α2 - AR拮抗剂的开发是新抗抑郁药的一个有吸引力的来源。本文描述了30种新型胍盐和2 - 亚氨基咪唑啉盐作为潜在α2 - AR拮抗剂的设计、合成及药理学评价。为了设计这一系列新的α2 - AR拮抗剂，使用GALAHAD软件开发了一个药效团模型。该研究表明，阳离子胍部分周围空间取代基的增加可能选择性地导致拮抗剂活性。在制备包含此特征的化合物并进行竞争性放射性配体结合以及[(35)S]GTPγS功能测定后发现，与之前观察到具有拮抗剂/激动剂活性混合物的类似未取代化合物相比，这种结构修饰仅产生α2 - AR拮抗剂。
