Thomas E. Cote

YM-09151-2: A potent antagonist for a peripheral D2-dopamine receptor

YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methyoxy-4-methylaminobenazamide) is a potent antagonist of the dopamine-induced inhibition of adenylate cyclase in the cholera toxin-treated intermediate lobe of the rat pituitary gland. In this system, YN-09151-2 (calculated Ki of 10.5 nM) is equipotent with fluphenazine as a dopamine antagonist. In contrast, YM-09151-2 is not a potent antagonist of the dopamine-induced stimulation of adenylate cyclase activity of fish retina or the dopamine-stimulated accumulation of cAMP in a preparation of dispersed fish retinal tissue. These observations suggest that YM-09151-2 is a potent antagonist of the D2-dopamine receptor (in the classification schema of Kebabian and Calne) and that YM-09151-2 may be a useful tool in pharmacological investigations of the D1- and the D2-receptor.

Dopamine receptors and cyclic AMP: a decade of progress

Abstract In the past decade, pharmacologist and biochemists have investigated the biochemical events initiated by stimulation of dopamine receptors. This review summarizes one aspect of these investigations — the regulation by dopamine receptors of adenylate cyclase, the enzyme synthesizing cyclic AMP.

Endogenous components of the striatum confer dopamine-sensitivity upon adenylate cyclase activity: The role of endogenous guanyl nucleotides

Repeated washing of the particulate material from rat striatum abolishes the dopamine-sensitivity of the adenylate cyclase activity. Readdition of the soluble fraction of the caudate homogenate restores the dopamine-sensitivity to the enzyme activity. Fractions, prepared with thin layer chromatography, containing endogenous GTP and GDP also restore dopamine-sensitivity to striatal adenylate cyclase activity. The effectiveness of GDP results from its conversion to GTP during the assay; when this conversion is eliminated, GDP can specifically block the coupling between the dopamine receptor and adenylate cyclase.

Beta-adrenergic receptor in the brain: comparison of 3H-dihydroalprenolol binding sites and a beta-adrenergic receptor regulating adenylyl cyclase activity in cell free homogenates.

Abstract The properties of specific 3H-dihydroalprenolol binding sites resemble the properties of the beta-receptor regulating hormone-sensitive adenylyl cyclase activity in an homogenate of rabbit cerebellum. The rabbit cerebellum has 5 to 6 pmole per gm (wet weight) of high affinity (KD=1.3 nM) specific binding sites for 3H-dihydroalprenolol. the interaction of several beta-adrenergic agonists and antagonists with the specific binding sites is rapid, reversible, and demonstrates stereospecificity which parallels the properties of the beta receptor. Beta-adrenergic agonists show a similar potency as agonists upon adenylyl cyclase activity and as inhibitors of 3H-dihydroalprenolol binding: i.e. l-isoproterenol > l-epinephrine > l-norepinephrine (suggesting a beta2 adrenergic receptor). The binding affinities of several beta-adrenergic agonists and antagonists for the specific binding sites approximate the affinities of these compounds for the stimulation of adenylyl cyclase. Thus, the 3H-dihydroalprenolol binding sites have properties similar to the beta-adrenergic receptor regulating adenylyl cyclase activity in a rabbit cerebellar homogenate.

Lisuride hydrogen maleate: An ergoline with β-adrenergic antagonist activity

Lisuride hydrogen maleate is identified as a potent beta-adrenergic antagonist using a hormone-sensitive adenylate cyclase system and [3H]dihydroalprenolol binding in cell free homogenates of rabbit cerebellum. Lisuride and two other ergolines, lergotrile and bromocriptine, and the phenothiazine, fluphenazine, all interact with spiroperidol binding sites (dopamine receptors) in the anterior pituitary; however, among these compounds lisuride is unique in its ability to antagonize the beta-adrenoceptor.