Antinociceptive activity of [beta-methyl-2 ',6 '-dimethyltyrosine(1)]-substituted cyclic [D-Pen(2),D-Pen(5)]enkephalin and [D-Ala(2),Asp(4)]deltorphin analogs

Research in our laboratories involves the development of selective opioid a gonists and antagonists as: 1) pharmacological tools to elucidate the mecha nisms of opioid antinociception, and 2) potential analgesics that possess t herapeutic advantages over currently available drugs. We hypothesized that the selectivity of peptide agonists toward the opioid receptor types and su btypes is topographically dependent. The current results assess the antinoc iceptive activity and opioid receptor selectivity of a series of beta-methy l-2',6'-dimethyltyrosine (TMT)-substituted cyclic [D-Pen(2),D-Pen(5)]enkeph alin (DPDPE) and [D-Ala(2),Asp(4)]deltorphin (DELT I) analogs. Compounds we re injected via the intracerebroventricular route into male ICR mice, and a ntinociception was assessed using the 55 degrees C warm water tail-flick te st. Antinociceptive A(50) values ranged from 0.35 to 17 nmol for the DELT I analogs and from 7.05 to >100 nmol for the DPDPE analogs. To test for rece ptor selectivity, mice were treated with selective mu- and delta-opioid ant agonists. In general, mu [beta-funaltrexamine (beta-FNA)]- and delta(1) ([D -Ala(2),Leu(5),Cys(6)] enkephalin)-antagonists blocked the antinociceptive actions of [TMT1]DPDPE analogs, whereas the antinociceptive actions of [TMT ]DELT I analogs were more sensitive to antagonism by the delta(2)-selective antagonist [Cys(4)]deltorphin and the mu-antagonist beta-FNA. The antinoci ceptive actions of the [(2R,3S)-TMT1]DELT I analog was suppressed by both [ D-Ala(2),Leu(5), Cys(6)]enkephalin and beta-FNA. These results are in contr ast to those found with the parent molecules DPDPE (primarily a delta(1) ag onist) and DELT I (a mixed delta(1)/delta(2) agonist). These results demons trate that topographical modification in position 1 of the DPDPE and DELT I peptides affects antinociceptive potency and opioid receptor selectivity.