Synthesis and biological profile of the enantiomers of [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin- 1-yl]furan-2-ylmethanone (cyclazosin), a potent competitive alpha 1B- adrenoceptor antagonist.
The enantiomers of [4-(4-amino-6, 7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin-1-yl]-fu ran- 2-ylmethanone (cyclazosin, 1) were synthesized from the chiral furan-2-yl(cis-octahydroquinoxalin-1-yl)methanone [(+)-2 and (-)-2], which were obtained by resolution of the racemic amine with (S)-(+)- and (R)-(-)-mandelic acid. The binding profile of the enantiomers of 1 was assessed at alpha 1-, alpha 2-, D2, and 5-HT1A receptors as well as at native alpha 1A- and alpha 1B- and cloned alpha 1a-, alpha 1b-, and alpha 1d-adrenoceptor subtypes in comparison with prazosin, spiperone, and AH11110A. (+)-1 displayed a 40-90-fold selectivity for the alpha 1B(alpha 1b)-adrenoceptor relative to alpha 1A(alpha 1a) and alpha 1d subtypes. A significant enantioselectivity was observed at the alpha 1A(alpha 1a)-adrenoceptor and particularly at alpha 1d-adrenoceptors since (-)-1 was 11-14- and 47-fold, respectively, more potent than (+)-1. Furthermore the enantiomer (+)-1 displayed selectivities of 1100-, 19000-, and 12000-fold in binding to alpha 1b-adrenoceptors relative to alpha 2-adrenoceptors and 5-HT1A and D2 receptors. These results indicate that (+)-1, [(+)-cyclazosin] is the most potent and selective ligand for the alpha 1B-adrenoceptor subtype so far described and may be a valuable tool in the characterization of alpha 1-adrenoceptor subtypes.
Giardinà
D
D
Department of Chemical Sciences, University of Camerino, Italy.
Crucianelli
M
M
Romanelli
R
R
Leonardi
A
A
Poggesi
E
E
Melchiorre
C
C
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D019556:COS Cells; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013237:Stereoisomerism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D011799:Quinazolines; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; C080462:cyclazosin