328409-99-0Relevant articles and documents
Synthesis and structure-activity relationships of a new model of arylpiperazines. 5. Study of the physicochemical influence of the pharmacophore on 5-HT1A/α1-adrenergic receptor affinity: Synthesis of a new derivative with mixed 5-HT1A/D2 antagonist properties
López-Rodríguez,Morcillo,Fernández,Porras,Orensanz,Beneytez,Manzanares,Fuentes
, p. 186 - 197 (2001)
In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT1A and α1-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin 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 receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT1A and α1-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 relationships (QSAR) and neural networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT1A: Ki = 27 nM; α1: Ki > 1000 nM). This derivative displays affinity for the dopamine D2 receptor (Ki = 22 nM) and is selective versus all other receptors examined (5-HT2A, 5-HT3, 5-HT4 and Bz; Ki > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT1A receptor sites and as an antagonist in the dopamine D2 receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT1A/D2 antagonist properties and this derivative could be useful as a pharmacological tool.
