Moon M W, Morris J K, Heier R F, Hsi R S, Manis M O, Royer M E, Walters R R, Lawson C F, Smith M W, Lahti R A
Department of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001.
Drug Des Discov. 1993;9(3-4):313-22.
(R)-5-(Dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]-quinolin-2( 1H)-on e (1a, U-86170), a potent high intrinsic activity dopamine (D2) agonist, has been prepared in eleven steps from quinoline. In several tests, the compound showed dopamine autoreceptor agonist activity at low doses. It showed postsynaptic agonist activity at somewhat higher doses, reversing the effects of reserpine in mice and increasing striatal acetylcholine levels. The compound showed some serotonergic (5HT1A) activity, but was inactive at other receptors. The related monopropylamine 2 (U-91356), also showed good dopaminergic agonist activity, and had improved metabolic stability and oral bioavailability in the rat and monkey when compared to 1a. Compounds 1a and 2 have been prepared in tritiated form, and [3H]1a (69 Ci/mmol) has found use as a D2 agonist radioligand in binding assays. The dopaminergic (D2) and serotonergic (5HT1A) activities of a series of compounds related to 1a have been evaluated using this ligand, [3H]raclopride, and [3H]8-OH DPAT.
(R)-5-(二丙基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(1a，U-86170)是一种强效的高内在活性多巴胺(D2)激动剂，已从喹啉出发经十一步反应制得。在多项试验中，该化合物在低剂量时表现出多巴胺自身受体激动剂活性。在稍高剂量时表现出突触后激动剂活性，可逆转利血平对小鼠的作用并提高纹状体乙酰胆碱水平。该化合物表现出一定的血清素能(5HT1A)活性，但对其他受体无活性。相关的单丙胺2(U-91356)也表现出良好的多巴胺能激动剂活性，与1a相比，在大鼠和猴子中具有更高的代谢稳定性和口服生物利用度。化合物1a和2已制备成氚标记形式，[3H]1a(69 Ci/mmol)已被用作结合试验中的D2激动剂放射性配体。已使用该配体、[3H]雷氯必利和[3H]8-羟基二丙胺来评估一系列与1a相关化合物的多巴胺能(D2)和血清素能(5HT1A)活性。
