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[摘要]：We have explored the concept of a molecular extender arm attached to a kappa opioid agonist pharmacophore 3 (ICI-199,441) in an effort to potentially interact, with a complementary group on a neighboring opioid receptor. The containing a terminal amine group was lengthened incrementally from 11 1 up to 18 atoms. Increasing the number-of atoms in the arm produced virtually no change in the mouse intracerebroventricular (i.c.v.) antinociceptive potency In contrast, the intrathecal (i.t.) potency of 6 (KDA-16) with a 16 atom arm was dramatically increased, as reflected by its antinociceptive i.c.v./i.t. ED50 ratio of similar to 130. Further lengthening led to a decreased ED50 ratio. In vivo selective antagonist studies of KDA-16 revealed that kappa and delta opioid receptors were responsible for the greatly enhanced it potency Calcium release experiments in HEK-293 cells suggested that KDA-16 selectively activate kappa-delta heteromers. These data are consistent with the reported possible presence of heteromeric kappa-delta opioid receptors in mouse spinal cord but not in the brain. The use of a molecular extender arm may be useful for developing spinally selective analgesics. |
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