Antinociceptive activity of [β-methyl-2',6'-dimethyltyrosine1]- substituted cyclic [D-Pen2,D-Pen5]enkephalin and [D-Ala2,Asp4]deltorphin analogs

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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 β-methyl-2',6'-dimethyltyrosine (TMT)-substituted cyclic [D- Pen2,B-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 δ-opioid antagonists. In general, μ [β-funaltrexamine (β-FNA)]- and δ1 ([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 δ2-selective antagonist [Cys4]deltorphin and the μ-antagonist β-FNA. The antinociceptive actions of the [(2R,3S)TMT1]DELT I analog was suppressed by both [D-Ala2,Leu5, Cys6]enkephalin and β-FNA. These results are in contrast to those found with the parent molecules DPDPE (primarily a δ1 agonist) and DELT I (a mixed δ12 agonist). These results demonstrate that topographical modification in position 1 of the DPDPE and DELT I peptides affects antinociceptive potency and opioid receptor selectivity.

Original languageEnglish (US)
Pages (from-to)151-158
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Apr 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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