21091-60-1

The docking of several 1-benzyl-4-arylpiperazines to the dopamine receptor (DAR) D2 was examined. The results demonstrated that the interaction of protonated N1 of the piperazine ring with Asp 86 (III.32) and edge-to-face interactions of the aromatic ring of the arylpiperazine part of the ligand with Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) of the receptor, represent the major stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could build one more hydrogen bond with Trp 182 (VI.48). Bulky substituents in position 4 were not tolerated due to the unfavorable sterical interaction with Phe 178 (VI.44). Substituents in position 2 and 3 were found to be sterically well tolerated. Introduction of electron attractive -NO2 group in position 3 of arylpiperazines decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity comparing to that of the phenylpiperazine 1. This can be explained in terms of favoured edge-to-face interactions in ligands with a high negative electrostatic surface potential (ESP) in the centre of aromatic residue of arylpiperazines. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands to form complexes with the DAR D2. Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) can be considered as a part of the ancillary DAR D2 pocket preserved in most G protein-coupled receptors of the A class and obviously, the arylpiperazine structural motif represents one of the privileged structures that bind to this pocket.

Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonist as well as templates for the future design of novel dopaminergic agents.

Reaction of lithiated dialkylamines with methoxy aromatics in refluxing THF leads to products resulting from a direct ipso-substitution.Especially with lithiated secondary amines high conversions and selectivities are achieved.Sulfonyl-substituted aromatics react equally well, but halogenated aromatics give rise to side-products arising from a competing pathway via aryne intermediates.The scope and mechanistic implications of this novel nucleophilic amination reaction are described.

The development of a facile, single-step method for the synthesis of 1,4-disubstituted piperazine-2,6-diones (4) in excellent yields from the corresponding aliphatic, aromatic and heteroaromatic primary amines and iminodiacetic acids (1) is described.A possible mechanism is discussed and the presence of intermediate 6a is confirmed by high-resolution proton NMR spectroscopy.The subsequent two-step conversion of dione 4a into the deoxygenated 4-unsubstituted piperazine 10 in high yield provides an attractive alternative to the currently available (hetero)arylpiperazine synthetic methods.

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