[L-ALA(3)]DPDPE - A NEW ENKEPHALIN ANALOG WITH A UNIQUE OPIOID RECEPTOR ACTIVITY PROFILE - FURTHER EVIDENCE OF DELTA-OPIOID RECEPTOR MULTIPLICITY

To investigate delta-opioid receptor topography near the 3-position of [D-Pen(2),D-Pen(5)] enkephalin (DPDPE), a series of small-group 3-pos ition analogs of DPDPE have been synthesized and assayed for binding p otencies and in vitro biological activities. L-Amino acid substitution s at this position are highly favored over D-amino acid substitutions, with the smallest, [L-Ala(3)]DPDPE(DPADPE), being the most favored in the series investigated. [L-Ala(3)]DPDPE is nearly as delta-potent an d more delta-selective in both rat brain binding (18 nM vs [H-3][p-ClP he(4)]DPDPE and mu/delta = 610) and peripheral bioassays (12 nM in the MVD and GPI/MVD = 4500) when compared to DPDPE (8.5 nM, mu/delta = 73 and 4.1 nM, GPI/MVD = 1800, respectively). Whereas DPDPE is a potent analgesic when given icv, [L-Ala(3)]DPDPE is only a weak analgesic. Ho wever, [L-Ala(3)]DPDPE has been found to antagonize DPDPE, but not Del torphin II, in a moderately potent (pA(2) = 5.7) and selective fashion in vivo. Thus, [L-Ala(3)]DPDPE is a fairly potent agonist at peripher al delta receptors and is a moderately potent (mixed) antagonist of de lta(1) receptors in the brain. It appears that [L-Ala(3)]DPDPE does no t interact in any significant manner with delta(2) or mu receptors in the brain.