Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists.
OBJECTIVE
To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor.


RESULTS
Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities.


CONCLUSIONS
the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K(i)beta(2)-AR=0.28microm, K(i)beta(1)-AR/K(i)beta(2)-AR=573, EC(50cAMP)=3.9nm, EC(50cardio)=16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.
Jozwiak
Krzysztof
K
Department of Chemistry, Medical University of Lublin, Lublin, Poland. krzysztof.jozwiak@umlub.pl
Woo
Anthony Yiu-Ho
AY
Tanga
Mary J
MJ
Toll
Lawrence
L
Jimenez
Lucita
L
Kozocas
Joseph A
JA
Plazinska
Anita
A
Xiao
Rui-Ping
RP
Wainer
Irving W
IW
D058666:Adrenergic beta-2 Receptor Agonists; D001665:Binding Sites; D002460:Cell Line; D005280:Fenoterol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018343:Receptors, Adrenergic, beta-2 / Q000276:immunology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol