Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding.

Article Details

Citation

Jasper JR, Lesnick JD, Chang LK, Yamanishi SS, Chang TK, Hsu SA, Daunt DA, Bonhaus DW, Eglen RM

Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding.

Biochem Pharmacol. 1998 Apr 1;55(7):1035-43.

PubMed ID
9605427 [ View in PubMed
]
Abstract

Alpha-2 adrenergic receptors (alpha2 AR) mediate incorporation of guanosine 5'-O-(gamma-thio)triphosphate ([35S]GTPgammaS) into isolated membranes via receptor-catalyzed exchange of [35S]GTPgammaS for GDP. In the current study, we used [35S]GTPgammaS incorporation to characterize the intrinsic activity and potency of agonists and antagonists at the cloned mouse alpha2a/d and human alpha2a, alpha2b, and alpha2c ARs. Full agonists increased [35S]GTPgammaS binding to membranes by 2- to 3-fold. Antagonists did not increase [35S]GTPgammaS binding but competitively inhibited agonist-stimulated [35S]GTPgammaS binding. Compounds with intrinsic activities less than that of the full agonists norepinephrine (NE) or epinephrine (EPI) were capable of antagonizing agonist-stimulated [35S]GTPgammaS binding. The agonistic properties of a number of alpha2 AR ligands were characterized at each alpha2 AR subtype. The rank order of agonist potency for selected compounds at the human receptors (with intrinsic activity compared with NE, defined as 1.0) was: alpha2a: Dexmedetomidine (0.73) > guanabenz (0.38) > UK-14304 (1.02) > clonidine (0.32) > ST-91 (0.63) > NE (1.00). alpha2b: Dexmedetomidine (1.10) > clonidine (0.18) > guanabenz (0.71) > NE (1.00) > ST-91 (0.44) > UK-14304 (0.59). alpha2c: Dexmedetomidine (1.03) > NE (1.00) > UK-14304 (0.75) > ST-91 (0.32) > or = clonidine (0.23) >> guanabenz (0). This report provides a functional characterization of adrenergic receptor ligands at human and mouse alpha2a/d AR. It also illustrates the utility of [35S]GTPgammaS incorporation as a functional marker of receptor activation.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BrimonidineAlpha-2A adrenergic receptorKi (nM)213.8N/AN/ADetails
BrimonidineAlpha-2B adrenergic receptorKi (nM)954.99N/AN/ADetails
BrimonidineAlpha-2C adrenergic receptorKi (nM)1949.84N/AN/ADetails
ClonidineAlpha-2A adrenergic receptorKi (nM)61.66N/AN/ADetails
ClonidineAlpha-2B adrenergic receptorKi (nM)69.18N/AN/ADetails
ClonidineAlpha-2C adrenergic receptorKi (nM)134.9N/AN/ADetails
DexmedetomidineAlpha-2A adrenergic receptorKi (nM)13.18N/AN/ADetails
GuanabenzAlpha-2A adrenergic receptorKi (nM)21.88N/AN/ADetails
GuanabenzAlpha-2B adrenergic receptorKi (nM)281.84N/AN/ADetails
GuanfacineAlpha-2A adrenergic receptorKi (nM)93.33N/AN/ADetails
GuanfacineAlpha-2B adrenergic receptorKi (nM)1380.38N/AN/ADetails
LofexidineAlpha-2A adrenergic receptorKi (nM)14.45N/AN/ADetails
NaphazolineAlpha-2A adrenergic receptorKi (nM)20.89N/AN/ADetails
OxymetazolineAlpha-2A adrenergic receptorKi (nM)7.24N/AN/ADetails
OxymetazolineAlpha-2B adrenergic receptorKi (nM)1778.28N/AN/ADetails
OxymetazolineAlpha-2C adrenergic receptorKi (nM)239.88N/AN/ADetails
PrazosinAlpha-2A adrenergic receptorKi (nM)794.33N/AN/ADetails
PrazosinAlpha-2B adrenergic receptorKi (nM)89.13N/AN/ADetails
XylometazolineAlpha-2A adrenergic receptorKi (nM)15.14N/AN/ADetails
XylometazolineAlpha-2B adrenergic receptorKi (nM)1047.13N/AN/ADetails
XylometazolineAlpha-2C adrenergic receptorKi (nM)128.82N/AN/ADetails
YohimbineAlpha-2A adrenergic receptorKi (nM)1.2N/AN/ADetails
YohimbineAlpha-2B adrenergic receptorKi (nM)1.2N/AN/ADetails
YohimbineAlpha-2C adrenergic receptorKi (nM)0.55N/AN/ADetails