Synthesis and structure-activity relationships of a new model of arylpiperazines. 5. Study of the physicochemical influence of the pharmacophore on 5-HT1A/alpha(1)-adrenergic receptor affinity: Synthesis of a new derivative with mixed 5-HT1A/D-2 antagonist properties

In this paper we have designed and synthesized a test series of 32 amide ar ylpiperazine derivatives VI in order to gain insight into the physicochemic al influence of the pharmacophores of 5-HT1A and alpha (1)-adrenergic recep tors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydanto in or a diketopiperazine (X = -(CH2)(3)-, -(CH2)(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both re ceptors, and the aromatic substituent R occupies the ortho- or meta-positio n and has been selected from a database of 387 substituents using the EDISF AR program. The 5-HT1A and alpha (1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationship s (QSAR) and neural-networks models for both receptors (following paper). A comparison of these models gives information for the design of the new lig and EF-7412 (46) (5-HT1A: K-i = 27 nM; alpha (1): K-i > 1000 nM). This deri vative displays affinity for the dopamine D-2 receptor (K-i = 22 nM) and is selective versus all other receptors examined (5-HT2A, 5-HT3, 5-HT4 and Bz ; K-i > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and po stsynaptic 5-HT1A receptor sites and; as an antagonist in the dopamine D-2 receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT1A/D-2 antagoni st properties and this derivative could be useful as a pharmacological tool .