Synthesis and Structure−Activity Relationship of Fluoro Analogues of 8-{2-[4-(4-Methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as Selective α1d-Adrenergic Receptor Antagonists

We have discovered high-affinity antagonists (exemplified by 11 and 12) that are the most selective for alpha(1d)-adrenergic receptors (alpha(1d)-AR) reported to date. In cloned receptor assay systems, 12 displays at least 95-fold selectivity for the alpha(1d)-AR over all other G-protein-coupled receptors tested, and the subtype selectivity of 11 was confirmed in pharmacologically defined isolated tissue preparations.