Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor.
Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the beta2 adrenergic receptor (Kibeta2-AR), the subtype selectivity relative to the beta1-AR (Kibeta1-AR/Kibeta2-AR) and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolar binding affinities were observed for (R,R)-fenoterol, the (R,R)-isomer of the p-methoxy, and (R,R)- and (R,S)-isomers of 1-naphthyl derivatives and all of these compounds were active at submicromolar concentrations in cardiomyocyte contractility tests. The Kibeta1-AR/Kibeta2-AR ratios were >40 for (R,R)-fenoterol and the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. The binding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting model indicated that the fenoterol derivatives interacted with two separate binding sites and one steric restricted site on the pseudo-receptor and that the chirality of the second stereogenic center affected Kibeta2 and subtype selectivity.
Jozwiak
Krzysztof
K
Department of Chemistry, Medical University of Lublin, Lublin, Poland.
Khalid
Chakir
C
Tanga
Mary J
MJ
Berzetei-Gurske
Ilona
I
Jimenez
Lucita
L
Kozocas
Joseph A
JA
Woo
Anthony
A
Zhu
Weizhong
W
Xiao
Rui-Ping
RP
Abernethy
Darrell R
DR
Wainer
Irving W
IW
D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D005280:Fenoterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol