[l-Ala³]DPDPE: A New Enkephalin Analog with a Unique Opioid Receptor Activity Profile. Further Evidence of δ-Opioid Receptor Multiplicity

To investigate δ-opioid receptor topography near the 3-position of [D-Pen²,D-Pen⁵]enkephalin (DPDPE), a series of small-group 3-position analogs of DPDPE have been synthesized and assayed for binding potencies and in vitro biological activities. l-Amino acid substitutions at this position are highly favored over D-amino acid substitutions, with the smallest, [l-Ala³]DPDPE (DPADPE), being the most favored in the series investigated, [l-Ala³] DPDPE is nearly δ-potent and more δ-selective in both rat brain binding (18 nM vs [³H] [p-CIPhe⁴]DPDPE and μ/δ = 610) and peripheral bioassays (12 nM in the MVD and GPI/MVD = 4500) when compared to DPDPE (8.5 nM, μ/δ = 73 and 4.1 nM, GPI/MVD = 1800, respectively). Whereas DPDPE is a potent analgesic when given icv, [l-Ala³] DPDPE is only a weak analgesic. However, [l-Ala³] DPDPE has been found to antagonize DPDPE, but not Deltorphin II, in a moderately potent (pA₂ = 5.7) and selective fashion in vivo. Thus, [l-Ala³] DPDPE is a fairly potent agonist at peripheral δ receptors and is a moderately potent (mixed) antagonist of δ₁ receptors in the brain. It appears that [l-Ala³]DPDPE does not interact in any significant manner with δ₂ or μ receptors in the brain.