RT Journal Article
SR Electronic
T1 Pharmacological Properties of [3H]Dihydroergokryptine Binding Sites Associated with Alpha Noradrenergic Receptors in Rat Brain Membranes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 38
OP 49
VO 14
IS 1
A1 DAVID A. GREENBERG
A1 SOLOMON H. SNYDER
YR 1978
UL http://molpharm.aspetjournals.org/content/14/1/38.abstract
AB [3H]Dihydroergokryptine, a mixed agonist-antagonist at alpha noradrenergic receptors, binds in saturable fashion and with high affinity to membranes of rat cerebral cortex. Saturation studies reveal a dissociation constant (KD) of 1.6 nM and a receptor density of 21 pmoles/g, similar to the sum of the maximal number of binding sites observed for the [3H]alpha agonist clonidine and the [3H]alpha antagonist WB-4101 alone. The relative affinities of a wide range of drugs indicate that binding to cerebral cortical membranes selectively involves alpha noradrenergic receptors. Dopamine and serotonin inhibit binding only weakly, indicating that labeling of receptors for these neurotransmitters is negligible. The regional distribution of [3H]dihydroergokryptine binding in rat brain coincides with that observed for alpha receptor binding of [3H]clonidine and [3H]WB-4101, except for disproportionately high levels in corpus striatum. This suggests that in striatal membranes [3H]dihydroergokryptine is able to bind to dopamine as well as alpha receptors. The slopes of logit-log plots for the inhibition of [3H]dihydroergokryptine binding by mixed agonist-antagonists are about 1.0, while pure agonists or antagonists display shallower inhibition curves. These data are consistent with a model of the alpha noradrenergic receptor in which agonists and antagonists bind selectively to discrete, noninterconverting sites, while mixed agonist-antagonists can bind to either site. ACKNOWLEDGMENTS We thank Dr. David C. U'Prichard and Stephen J. Peroutka for their helpful advice, and Mr. Gregory Mack for his skillful assistance. Drs. N. J. M. Birdsall and D. Rodbard provided helpful suggestions concerning analysis of data.