[L-Ala3]DPDPE: a new enkephalin analog with a unique opioid receptor activity profile. Further evidence of delta-opioid receptor multiplicity.

To investigate δ-opioid receptor topography near the 3-position of [D-Pen 2 ,D-Pen 5 ]enkephanlin (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-Ala 3 ]DPDPE (DPADPE), being the most favored in the series investigated. [L-Ala 3 ]DPDPE is nearly as δ-potent and more δ-selective in both rat brain binding and peripheral bioassays when compared to DPDPE. Whereas DPDPE is a potent analgesic when given icv, [L-Ala 3 ]DPDPE is only a weak analgesic. However, [L-Ala 3 ]DPDPE has been found to antagonize DPDPE, but not Deltorphin II, in a moderately potent and selective fashion in vivo. Thus, [L-Ala 3 ]DPDPE is a fairly potent agonist at peripheral δ receptors and is a moderately potent (mixed) antagonist of δ 1 receptors in the brain. It appears that [L-Ala 3 ]DPDPE does not interact in any significant manner with δ 2 or μ receptors in the brain