Influence of lipophilicity and chirality on the selectivity of ligands for beta 1- and beta 2-adrenoceptors.
Eudismic and QSAR analyses are reported for the beta 1- and beta 2-adrenoceptor affinities and beta 1-selectivity of 10 enantiomeric pairs of ligands with only N-isopropyl or N-t-butyl groups. For both receptors, the eudismic index (ratio of affinity) increases with the affinity of the eutomers. However, the affinity of the distomers for the beta 2-adrenoceptor is relatively high, suggesting additional hydrophobic interactions. This is confirmed by various correlations between affinities and lipophilicities, showing that the affinity for beta 2-adrenoceptors is slightly more dependent on lipophilicity than that for beta 1-adrenoceptors. As a result, the beta 1-selectivity of the investigated beta 1-adrenoceptor ligands is strongly and negatively correlated with their lipophilicity (r = -0.942).
el Tayar
N
N
School of Pharmacy, University of Lausanne, Switzerland.
Testa
B
B
van de Waterbeemd
H
H
Carrupt
P A
PA
Kaumann
A J
AJ
D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D008024:Ligands; D008055:Lipids; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012995:Solubility; D013237:Stereoisomerism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D008024:Ligands; D008055:Lipids; D011943:Receptors, Adrenergic, beta