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

The analgesic activity and opioid receptor binding characteristics were stu died for the isothiocyanate ohmefentanyl (OMFIT), and isothiocyanate carfen tanil (CarFIT), isothiocyanate 4-methoxymethylfentanyl (MethoFIT), isothioc yanate 3-methylfentanyl (superFIT) and their amide analogs. Antinociceptive activity was evaluated using the mouse hot plate test; selectivity for opi oid receptor was determined in bioassay and binding assay. SuperFIT, CarFIT , OMFIT and MethoFIT exhibited an analgesic ED50 lower than those of their parent compounds without isothiocyanate (SCN) group. Furthermore these comp ounds exhibited potent inhibitory actions on the electrically evoked contra ctions 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 [H-3]OMF to mouse brain membrane was weaker than those of their parent compounds withou t SCN-group. CarFIT and MethoFIT showed weaker inhibitory actions on the bi nding of [H-3] DADLE than their parent compounds without SCN-group, but Sup erFIT and OMFIT stronger than their parent compounds, 3-methylfentanyl and ohmefentanyl. The selectivity of these isothiocyanate derivatives for delta opioid receptors increased. In conclusion, introducing isothiocyanato-grou p into 1-position of phenyl ring of ohmefentanyl and other fentanyl analogs would enhance the selectivity of these compounds for delta-opioid receptor s, but decrease their analgesic activity.