Abstract
A lanthionine enkephalin derivative, Tyr-c[d-ValL-Gly-Phe-d-AlaL]-OH (DVL2DAL5LanEnk), where ValL and AlaL denote the lanthionine amino acid ends linked via a monosulfide bridge to form the lanthionine structure, was synthesized. It was found to possess selectivity for and potency at the δ versus μ opioid receptor as defined by binding studies and by its respective activity on the mouse vas deferens compared with the guinea pig ileum. The agent produced a potent analgesia after intrathecal and intraperitoneal delivery with ED50 values being, respectively, 0.19 μg and 0.49 mg/kg. The effects of the agent were reversed by the δ-selective antagonist naltrindole. These analgesic actions occurred at doses that had no effect upon general behavior or motor function. These results suggest a potent δ-preferring agent suitable for development as a systemic δ opioid analgesic.
Footnotes
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DOI: 10.1124/jpet.102.039750
- Abbreviations:
- TAN-67
- (4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine
- BW373U86
- (+/−)-4-[(R*)-[(2S*,5R*)-2,5-dimethyl-4-(2-propenyl)-1- piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride
- SNC-80
- (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide
- DVL2DAL5LanEnk
- Tyr-c[d-ValL-Gly-Phe-d-AlaL]-OH
- CTOP
- d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2
- NTI
- naltrindole hydrochloride
- GPI
- guinea pig ileum
- MVD
- mouse vas deferens
- DPDPE
- [d-Pen2,d-Pen5]-enkephalin
- %MPE
- percent maximal possible effect
- Received July 11, 2002.
- Accepted October 14, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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