ABSTRACT
Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
Subject(s)
Adrenergic alpha-1 Receptor Antagonists , Adrenergic alpha-Antagonists/chemical synthesis , Amides/chemical synthesis , Piperazines/chemical synthesis , Propylamines/chemical synthesis , Urinary Bladder/drug effects , Adolescent , Adrenergic alpha-Antagonists/pharmacology , Adrenergic alpha-Antagonists/therapeutic use , Adult , Aged , Amides/pharmacology , Amides/therapeutic use , Animals , Binding, Competitive , Humans , Male , Middle Aged , Models, Chemical , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Piperazines/pharmacology , Piperazines/therapeutic use , Prazosin/metabolism , Propylamines/pharmacology , Propylamines/therapeutic use , Prostatic Hyperplasia/drug therapy , Rabbits , Rats , Structure-Activity Relationship , Urinary Bladder/metabolismABSTRACT
Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
