title: CoMFA analysis of the human beta(1)-adrenoceptor binding affinity of a series of phenoxypropanolamines.
abstract: A series of 36 phenoxypropanolamines was examined to determine the structure--activity relationships of beta-adrenoceptor (beta-AR) antagonists for the human beta(1)-AR. The binding affinities of all the compounds were determined for human beta(1)-ARs expressed in Chinese hamster ovary cells and the antagonist potency for rat atrial beta(1)-ARs was determined for 32 of these compounds for comparative purposes. The compounds, based upon a phenoxypropanolamine core structure with various meta-, ortho-, para- and amine-substituents, displayed binding affinities (pK(i)) for the human beta(1)-AR ranging from 5.49 to 9.35. Antagonist potencies (pA(2)) in the rat ranged from 5.52 to 9.56 and correlated with the human binding affinities (r(2)=0.86). Twenty-six compounds were used as the training set for comparative molecular field analysis (CoMFA) of antagonist binding affinity at the human beta(1)-AR and also of antagonist potency for rat atrial beta(1)-ARs. The CoMFA models were derived using both the CoMFA electrostatic and steric field parameters. The initial human beta(1)-AR model (n=26, q(2)=0.59, ONC=6, SE(CV)=0.70, r(2)=0.98, SE(non-CV)=0.16, F(6,19)=148) predicted the binding affinities of seven out of ten test compounds, not included in the training set, with residual pK(i) values less-than-or-equal0.50. The final human beta(1)-AR model (n=36, q(2)=0.66, ONC=5, SE(CV)=0.61, r(2)=0.95, SE(non-CV)=0.24, F(5,30)=107), consisting of the training set plus the test set of compounds, may prove useful in the design of new phenoxypropanolamine type beta(1)-AR antagonists. The initial rat beta(1)-AR model (n=26, q(2)=0.42, ONC=6, SE(CV)=0.76, r(2)=0.94, SE(non-CV)=0.25, F(6,19)=47) predicted the affinities of five out of six test compounds with residual pA(2) values less-than-or-equal0.50. The final rat beta(1)-AR model (i.e. training set plus test set of compounds) (n=32, q(2)=0.38, ONC=5, SE(CV)=0.69, r(2)=0.93, SE(non-CV)=0.24, F(5,26)=67) in particular has a low q(2) value, indicating that, at least for the rat, the biologically active phenoxypropanolamine conformation may be quite different to the low energy extended conformation chosen for this CoMFA study.
authors.affiliation: Department of Medicine, Clinical Pharmacology and Therapeutics Unit, The University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, 3084 Victoria, Australia.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Louis
authors.forename: Linda A
authors.initials: LA
authors.lastname: Rezmann-Vitti
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Nero
authors.forename: Dimitri
authors.initials: D
authors.lastname: Iakovidis
authors.forename: Graham P
authors.initials: GP
authors.lastname: Jackman
authors.forename: William J
authors.initials: WJ
authors.lastname: Louis
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006325:Heart Atria; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1