Analgesic activity and selectivity of isothiocyanate derivatives of fentanyl analogs for opioid receptors

• Published in: Life sciences (1973) 1999, Vol.65 (15), p.1589-1595
• Main Authors: Bi-Yi, Chen, Wen-Qiao, Jin, Jie, Chen, Xin-Jian, Chen, You-Cheng, Zhu, Zhi-Qiang, Chi
• Format: Article
• Language: English
• Subjects: Amides - metabolism; Amides - pharmacology; analgesia; Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacology; Animals; binding selectivity; bioassay; Fentanyl - analogs & derivatives; Fentanyl - metabolism; Fentanyl - pharmacology; fentanyl analogs; isothiocyanate derivatives; Isothiocyanates - metabolism; Isothiocyanates - pharmacology; Male; Mice; Muscle Contraction - drug effects; Nociceptors - drug effects; opioid receptors; Pain Measurement - drug effects; Receptors, Opioid - metabolism; Receptors, Opioid, delta - metabolism; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Vas Deferens - drug effects; Vas Deferens - physiology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(99)00404-X

The analgesic activity and opioid receptor binding characteristics were studied for the isothiocyanate ohmefentanyl (OMFIT), and isothiocyanate carfentanil (CarFIT), isothiocyanate 4-methoxymethylfentanyl (MethoFIT), isothiocyanate 3-methyl-fentanyl (superFIT) and their amide analogs. Antinociceptive activity was evaluated using the mouse hot plate test; selectivity for opioid receptor was determined in bioassay and binding assay. SuperFIT, CarFIT, OMFIT and MethoFIT exhibited an analgesic ED 50 lower than those of their parent compounds without isothiocyanate (SCN) group. Furthermore these compounds exhibited potent inhibitory actions on the electrically evoked contractions of mouse vas deferens, which could be antagonized by naloxone, but their actions were weaker than those of their parent compounds without SCN-group. The inhibitory actions of these compounds on binding of [ 3H]OMF to mouse brain membrane was weaker than those of their parent compounds without SCN-group. CarFIT and MethoFIT showed weaker inhibitory actions on the binding of [ 3H] DADLE than their parent compounds without SCN-group, but SuperFIT and OMFIT stronger than their parent compounds, 3-methylfentanyl and ohmefentanyl. The selectivity of these isothiocyanate derivatives for δ opioid receptors increased. In conclusion, introducing isothiocyanato-group into 1-position of phenyl ring of ohmefentanyl and other fentanyl analogs would enhance the selectivity of these compounds for δ-opioid receptors, but decrease their analgesic activity.