Agonist–antagonist properties of N-allyl-[D-Ala]²-Met-enkephalin

Abstract

RECEPTOR displacement of the opiate antagonist naloxone requires concentrations of morphine and other opiate alkaloids similar to those required to elicit analgesia^1–3 or inhibit ileal contraction^4–5. A new class of opiates with structures based on the discovery of endogenous, morphine-like pentapeptide—enkephalin⁶—also displace opiate receptor binding with potencies paralleling in vivo activities^7–10. Intrinsic activity (agonist or antagonist quality), a different dimension of opiate alkaloid effects in vivo, is closely correlated with the in vitro effects of sodium ion in the incubation medium: while antagonist binding to opiate receptors labelled by radioactive naloxone is almost unaffected by sodium ion addition, opiate alkaloid agonists become 10–60-fold weaker and mixed agonist–antagonists have intermediate downward shifts in apparent affinity after sodium ion addition^1,11. We present here an analysis of the sodium sensitivities of the major opiate peptides which have all been identified as ‘agonists’ thus far. In addition, we describe the synthesis, behavioural and in vitro receptor analysis of N-allyl-[D-Ala]²-Met-enkephalin (Fig. 1), a novel peptide whose structure was designed in analogy¹² with that of the alkaloid opiate antagonists¹³ in order to obtain a peptide opiate antagonist, if possible.