| Abstract
| - In the present study, more than 75 compounds structurally related to BMY 7378 have beendesigned and synthesized. Structural variations of each part of the reference molecule havebeen introduced, obtaining highly selective ligands for the α1d adrenergic receptor. The moleculardeterminants for selectivity at this receptor are essentially held by the phenyl substituent inthe phenylpiperazine moiety. The integration of an extensive SAR analysis with dockingsimulations using the rhodopsin-based models of the three α1-AR subtypes and of the 5-HT1Areceptor provides significant insights into the characterization of the receptor binding sites aswell as into the molecular determinants of ligand selectivity at the α1d-AR and the 5-HT1Areceptors. The results of multiple copies simultaneous search (MCSS) on the substitutedphenylpiperazines together with those of manual docking of compounds BMY 7378 and 69into the putative binding sites of the α1a-AR, α1b-AR, α1d-AR, and the 5-HT1A receptors suggestthat the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4,5, 6 and extracellular loop 2 (E2), whereas the spirocyclic ring of the ligand docks into a siteformed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SARdata produced in this work. Furthermore, the binding site of the imide moiety does not allowfor the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding interactions,consistent with the SAR data, in particular with the results obtained with the lactam derivative128. The results of docking simulations also suggest that the second and third extracellularloops may act as selectivity filters for the substituted phenylpiperazines. The most potent andselective compounds for α1d adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073),are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.
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