STRUCTURE AND SEROTONIN 5-HT2C RECEPTOR ACTIVITY OF ORTHO-SUBSTITUTEDAND META-SUBSTITUTED PHENYLPIPERAZINES

The structural characteristics of ortho- and meta-substituted phenylpi perazines have been investigated in order to understand their actions at the serotonin 5-HT2C receptor. The crystal structures of the 4-meth ylated analogues of two phenylpiperazines that are already known as 5- HT2C ligands, 1-(1-naphthyl)-4-methylpiperazine (1NMP) and 1-[(3-trifl uoromethyl)phenyl]-4-methylpiperazine (TFMPMP), and those of two novel 5-HT2C ligands, 1-(2-methoxyphenyl)piperazine (oMPP) and 1-(3-methoxy phenyl)piperazine (mMPP), are determined. Molecular mechanics calculat ions are performed to calculate the energy profiles of six phenylpiper azines for rotation about the central phenyl-nitrogen bond. The activi ties of several phenylpiperazines, in combination with their crystal s tructures and conformational characteristics, lead to the hypothesis t hat the conformation for which the piperazine ring and the phenyl ring are approximately co-planar should be the 5-HT2C receptor 'activating ' conformation. This hypothesis is then used to predict the activities of the two novel 5-HT2C ligands oMPP and mMPP. oMPP is predicted to b e an antagonist at this receptor, whereas mMPP is predicted to be an a gonist. As this prediction was confirmed by in vitro and in vivo tests , the proposed conformation is very likely to be responsible for the a ctivation of the 5-HT2C receptor.