Malcolm W. Moon

Pharmacology of U-91356A, an agonist for the dopamine D2 receptor subtype

U-91356A [(R)-5,6-dihydro-5-(propylamino)4H-imidazo[4,5,1-ij]quinolin -2-(1H)-one, monohydrochloride], bound with highest affinity to the dopamine D2 receptor subtype, although it also bound with somewhat lower affinities to the dopamine D3 and D4, as well as the 5-HT1A receptor subtypes. In addition to depressing dopamine synthesis and turnover, injection of U-91356A increased striatal acetylcholine concentrations. U-91356A also depressed firing rates of dopamine neurons. In mice, this compound stimulated cage climbing and locomotor activity in reserpinized animals; it also antagonized D-amphetamine-stimulated locomotor activity. It produced contralateral turning in rats with unilateral lesions of the substantia nigra. These data are consistent with roles for the dopamine D2 receptor subtype as a dopamine autoreceptor and as a stimulatory, postsynaptic dopamine receptor.

Dopamine D2 receptor binding properties of [3H]U-86170, a dopamine receptor agonist

U-86170F, an imidazoguinolinone, is a potent dopamine D2 agonist, binding with high affinity to the dopamine D2 receptor. A Kd of 0.99 nM was determined in membranes from Chinese hamster ovarian (CHO) cells transfected with the D2 receptor and a Kd of 1.72 nM was obtained in rat striatal homogenates. GTP sensitivity was demonstrated when its addition (300 microM) reduced [3H]U-86170 binding by 60%. This agonist ligand is especially effective in identifying agonists and partial agonists, as well as antagonists, and affords a more precise evaluation of their affinity for the dopamine D2 receptor, without the use of multiple site analysis, than does an antagonist [3H]-ligand.

An asymmetric synthesis of (R)‐5‐(methylamino)‐5,6‐dihydro‐4H‐imidazo‐[4,5,1‐ij]quinolin‐2(1H)‐one (1) and its [2‐14C]‐ and [6,7‐3H2]‐labeled forms

(R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine agonist which shows selectivity for the D2 receptor subtype, and is of interest as a potential drug for the treatment of Parkinsons disease. An asymmetric epoxidation approach has been used to prepare 1 in eleven steps (15% overall yield) from 8-nitroquinoline. An advanced intermediate in this synthesis, tert-butyl (R)-methyl(8-amino-1,2,3,4-tetrahydro-3-quinolinyl)carbamate (10), has been reacted with [ 14 C]phosgene to provide a two-step synthesis of 1 labeled with carbon-14 at the C-2 position (236 μCi/mg). Bromination of 1 gave the dibromo analogue 12b which was reduced in the presence of tritium gas to give 1 labeled with tritium at the C-6 and C-7 positions (28.5 Ci/mmol). In addition to providing syntheses for labeled forms of the drug which are useful in drug disposition and receptor binding studies, this approach also provides a convenient synthesis for the unlabeled form of drug

α‐Methyl analogues of acetylenic amines as striatal muscarinic antagonists

Abstract— The effect of acetylenic amines, with or without α‐methyl substitution, on striatal acetylcholine (ACh) concentration in rats was investigated. Oxotremorine, oxotremorine‐1, and U‐77053 (trimethyl (4‐(1‐pyrrolidinyl)‐2 butynyl)‐urea), the unsubstituted amines, increased striatal ACh concentration. On the other hand, the corresponding α‐methyl substituted analogues, α‐methyl‐oxotremorine, BM‐5, and α‐methyl U‐77053, decreased the concentration of ACh in the striatum. The results indicate that substitution of α‐methyl in acetylenic amines converts compounds from agonists to antagonists for striatal muscarinic receptors.