| 17034141 |
Hoglund IP, Silver S, Engstrom MT, Salo H, Tauber A, Kyyronen HK, Saarenketo P, Hoffren AM, Kokko K, Pohjanoksa K, Sallinen J, Savola JM, Wurster S, Kallatsa OA: Structure-activity relationship of quinoline derivatives as potent and selective alpha (2C)-adrenoceptor antagonists. J Med Chem. 2006 Oct 19;49(21):6351-63.
Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human alpha (2)-adrenoceptor subtypes (alpha (2A), alpha (2B), and alpha (2C)). A number of compounds with good antagonist potencies against the alpha (2C)-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl) phenylamino] quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the alpha (2C)-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the alpha (2C)-adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative. |
34(0,1,1,4) |