A series of novel arylpiperazine derivatives as α1A/1D-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards α1-ARs (α1A, α1B, and α1D). Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on α1A and/or α1D subtypes over α1B in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest α1A/D-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled α1-ARs (α1A, α1B, and α1D) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of α1A was validated as the key residues for binding ligand. This work provides useful information for finding more new potential drugs in clinic in treating benign prostatic hyperplasia (BPH).
Keywords: Antagonic activity; Arylpiperazine derivatives; Homology modeling; Structure–activity relationship; Subtype selectivity; α(1)-ARs.
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