title: Bioisosteric phentolamine analogs as selective human alpha(2)- versus alpha(1)-adrenoceptor ligands.
abstract: Phentolamine is known to act as a competitive, non-subtype-selective alpha-adrenoceptor antagonist. In an attempt to improve alpha(2)- versus alpha(1)-adrenoceptor selectivity and alpha(2)-adrenoceptor subtype-selectivity, two new chemical series of bioisosteric phentolamine analogs were prepared and evaluated. These compounds were evaluated for binding affinities on alpha(1)- (alpha(1A)-, alpha(1B)-, alpha(1D)-) and alpha(2)- (alpha(2A)-, alpha(2B)-, alpha(2C)-) adrenoceptor subtypes that had been stably expressed in human embryonic kidney and Chinese hamster ovary cell lines, respectively. Methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the alpha(2)- versus alpha(1)-adrenoceptors. Within the alpha(2)-adrenoceptors, these analogs bound with higher affinity at the alpha(2A)- and alpha(2C)-subtypes as compared to the alpha(2B)-subtype. In particular, the t-butyl analog was found to be the most selective, its binding at the alpha(2C)-adrenoceptor (Ki=3.6 nM) being 37- to 173-fold higher than that at the alpha(1)-adrenoceptors, and around 2- and 19-fold higher than at the alpha(2A)- and alpha(2B)-adrenoceptors, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities of selected compounds from the bioisosteric series on human alpha(1A)- and alpha(2C)-adrenoceptors. Thus, the results with these bioisosteric analogs of phentolamine provide a lead to the rational design of potent and selective alpha(2)-adrenoceptor ligands that may be useful in improving the therapeutic profile of this drug class for human disorders.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677, United States. supriya.bavadekar@stjude.org
authors.forename: Supriya A
authors.initials: SA
authors.lastname: Bavadekar
authors.forename: Seoung-Soo
authors.initials: SS
authors.lastname: Hong
authors.forename: Sang-Ii
authors.initials: SI
authors.lastname: Lee
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Feller
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D010646:Phentolamine / Q000031:analogs & derivatives* / Q000378:metabolism; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D020218:Response Elements; D013329:Structure-Activity Relationship
chemical_list: D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D000242:Cyclic AMP; D008156:Luciferases; D010646:Phentolamine