Vol. 293, Issue 1, 151-158, April 2000

Antinociceptive Activity of [-Methyl-2',6'-dimethyltyrosine¹]-Substituted Cyclic [D-Pen²,D-Pen⁵]Enkephalin and [D-Ala²,Asp⁴]Deltorphin Analogs¹

Edward J. Bilsky, Xinhua Qian, Victor J. Hruby and Frank Porreca

Department of Biological Sciences, University of Northern Colorado, Greeley, Colorado (E.J.B.); and Departments of Pharmacology (F.P.) and Chemistry (X.Q., V.J.H.), The University of Arizona, Tucson, Arizona

Research in our laboratories involves the development of selective opioid agonists and antagonists as: 1) pharmacological tools to elucidate the mechanisms of opioid antinociception, and 2) potential analgesics that possess therapeutic advantages over currently available drugs. We hypothesized that the selectivity of peptide agonists toward the opioid receptor types and subtypes is topographically dependent. The current results assess the antinociceptive activity and opioid receptor selectivity of a series of -methyl-2',6'-dimethyltyrosine (TMT)-substituted cyclic [D-Pen²,D-Pen⁵]enkephalin (DPDPE) and [D-Ala²,Asp⁴]deltorphin (DELT I) analogs. Compounds were injected via the intracerebroventricular route into male ICR mice, and antinociception was assessed using the 55°C warm water tail-flick test. Antinociceptive A₅₀ 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 receptor selectivity, mice were treated with selective µ- and -opioid antagonists. In general, µ [-funaltrexamine (-FNA)]- and ₁ ([D-Ala²,Leu⁵,Cys⁶] enkephalin)-antagonists blocked the antinociceptive actions of [TMT¹]DPDPE analogs, whereas the antinociceptive actions of [TMT¹]DELT I analogs were more sensitive to antagonism by the ₂-selective antagonist [Cys⁴]deltorphin and the µ-antagonist -FNA. The antinociceptive actions of the [(2R,3S)-TMT¹]DELT I analog was suppressed by both [D-Ala²,Leu⁵, Cys⁶]enkephalin and -FNA. These results are in contrast to those found with the parent molecules DPDPE (primarily a ₁ agonist) and DELT I (a mixed ₁/₂ agonist). These results demonstrate that topographical modification in position 1 of the DPDPE and DELT I peptides affects antinociceptive potency and opioid receptor selectivity.