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 alpha(1d)-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.
Konkel
Michael J
MJ
Lundbeck Research USA, Inc., 215 College Road, Paramus, New Jersey 07652, USA. miko@lundbeck.com
Wetzel
John M
JM
Cahir
Marie
M
Craig
Douglas A
DA
Noble
Stewart A
SA
Gluchowski
Charles
C
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C500630:8-(2-(4-(2,4,5-trifluorophenyl)piperazin-1-yl)-1-methylethyl)-8-azaspiro(4.5)decane-7,9-dione; C500629:8-(2-(4-(2,4,5-trifluorophenyl)piperazin-1-yl)ethyl)-8-azaspiro(4.5)decane-7,9-dione; C547719:ADRA1D protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D013141:Spiro Compounds