Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania 19104, United States.
ACS Chem Neurosci. 2021 Jun 16;12(12):2194-2201. doi: 10.1021/acschemneuro.1c00212. Epub 2021 May 27.
We previously reported that -(3-chlorophenyl)guanidine () represents a novel α7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure-activity relationship (SAR). Preliminary data suggested that the N-methyl analog of , , was several times more potent. Therefore, the chloro group at the aryl 3-position of and its N-methyl counterpart were replaced with a number of substituents considering the electronic, lipophilic, and steric nature of the substituents. The potencies of the compounds to inhibit acetylcholine (ACh)-induced responses were obtained in oocytes expressing human α7 nicotinic ACh receptors (nAChRs) using a two-electrode voltage-clamp assay. We found that the nature of the 3-position substituents had relatively little (i.e., <10-fold) effect on potency, and the presence of an N-isopropyl substituent was tolerated. Here, we report the first SAR investigation of this novel α7 nAChR antagonist chemotype.
我们之前报道过，（-（3-氯苯基）胍（）代表了一种新型的α7 烟碱型乙酰胆碱（nACh）受体拮抗剂化学型。在本研究中，合成了一系列化合物，旨在研究构效关系（SAR）。初步数据表明，的 N-甲基类似物，效力要强几倍。因此，考虑到取代基的电子、亲脂性和空间性质，用取代基取代了和其 N-甲基对应物 中芳基 3-位的氯原子。用在表达人α7 烟碱型乙酰胆碱受体（nAChRs）的卵母细胞中进行的双电极电压钳测定法，获得了抑制乙酰胆碱（ACh）诱导的反应的化合物的效力。我们发现 3-位取代基的性质对效力的影响相对较小（即<10 倍），并且可以容忍 N-异丙基取代基的存在。在这里，我们报告了这种新型的α7 nAChR 拮抗剂化学型的首次 SAR 研究。
