title: TH-030418: a potent long-acting opioid analgesic with low dependence liability.
abstract: Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to μ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K (i) values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED(50) values of 1.37 μg/kg and 1.70 μg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.
authors: Beijing Institute of Pharmacology & Toxicology, 27 Taiping Road, Beijing, People's Republic of China. yg1st@163.com
authors: Gang
authors: G
authors: Yu
authors: Ling-Di
authors: LD
authors: Yan
authors: Yu-Lei
authors: YL
authors: Li
authors: Quan
authors: Q
authors: Wen
authors: Hua-Jin
authors: HJ
authors: Dong
authors: Ze-Hui
authors: ZH
authors: Gong
references: J Pharm Pharmacol. 1995 Aug;47(8):669-73
references: 8583370
references: Eur J Pharmacol. 2001 Jul 6;423(2-3):157-66
references: 11448480
references: Neurosci Biobehav Rev. 1995 Spring;19(1):39-51
references: 7770196
references: J Pharmacol Exp Ther. 2007 Apr;321(1):227-36
references: 17220427
references: Annu Rev Pharmacol. 1971;11:241-70
references: 4948499
references: Neuropharmacology. 2005 Sep;49(4):439-46
references: 15919100
references: Zhongguo Yao Li Xue Bao. 1982 Jun;3(2):81-4
references: 6214153
references: J Am Chem Soc. 1967 Jun 21;89(13):3281-92
references: 6042764
references: J Pharmacol Exp Ther. 1997 Aug;282(2):676-84
references: 9262330
references: Acta Pharmacol Sin. 2004 Nov;25(11):1413-8
references: 15525461
references: J Pharmacol Exp Ther. 2001 Feb;296(2):528-36
references: 11160640
references: Lancet Oncol. 2005 Sep;6(9):696-704
references: 16129370
references: J Med Chem. 2004 Jun 3;47(12):2973-6
references: 15163178
references: Curr Opin Neurobiol. 2004 Jun;14(3):370-8
references: 15194118
references: Biol Pharm Bull. 1993 Aug;16(8):774-7
references: 8220323
references: J Pharmacol Exp Ther. 2007 Feb;320(2):934-43
references: 17132815
references: J Pharmacol Exp Ther. 2006 Jul;318(1):282-7
references: 16569757
references: Biol Pharm Bull. 1996 Mar;19(3):477-9
references: 8924922
references: Nature. 1996 Oct 31;383(6603):819-23
references: 8893006
references: Brain Res. 1999 Jun 19;832(1-2):168-70
references: 10375664
references: Eur J Pharmacol. 1997 Apr 18;324(2-3):141-5
references: 9145764
references: Br J Pharmacol. 2001 Sep;134(2):441-7
references: 11564664