Gogoi Sanjib, Biswas Swati, Modi Gyan, Antonio Tamara, Reith Maarten E A, Dutta Aloke K
Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202.
ACS Med Chem Lett. 2012 Oct 26;3(12):991-996. doi: 10.1021/ml3002117.
This report describes development of a series of novel bivalent molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT. Spacer length in the bivalent compounds had a pronounced influence on affinity for D2 receptors. A 23-fold increase of D2 affinity was observed at a spacer length of 9 or 10 (compounds 11d and 14b) compared to monovalent 5-OH-DPAT (Ki; 2.5 and 2.0 vs. 59 nM for 11d and 14b vs. 5-OH-DPAT, respectively). Functional potency of 11d and 14b indicated a 24- and 94-fold increase in potency at the D2 receptor compared to 5-OH-DPAT (EC50; 1.7 and 0.44 vs. 41 nM for 11d and 14b vs. 5-OH-DPAT, respectively). These are the most potent bivalent agonists for D2 receptor known to date. This synergism is consonant with cooperative interaction at the two orthosteric binding sites in the homodimeric receptor.
本报告描述了一系列新型二价分子的开发,其药效团源自D2/D3激动剂5-羟基-DPAT。二价化合物中的间隔长度对D2受体亲和力有显著影响。与单价5-羟基-DPAT相比,间隔长度为9或10时(化合物11d和14b),观察到D2亲和力增加了23倍(11d和14b的Ki分别为2.5和2.0 nM,而5-羟基-DPAT为59 nM)。11d和14b的功能效力表明,与5-羟基-DPAT相比,在D2受体上的效力分别增加了24倍和94倍(11d和14b的EC50分别为1.7和0.44 nM,而5-羟基-DPAT为41 nM)。这些是迄今为止已知的对D2受体最有效的二价激动剂。这种协同作用与同二聚体受体中两个正构结合位点的协同相互作用一致。