A. W. Lipkowski

Opioid and neurokinin activities of substance P fragments and their analogs

Newly developed substance P (SP) analogs with altered N-terminal sequences which equalize the lipophilicity of the N-terminal and C-terminal elements and of their fusion product were examined using i.t. injection in mice. I.t. injection of either the full length analog or the C-terminal hexapeptide (CP) produced biting and scratching behavior similar to that elicited by SP. SPF was approximately 5-fold and CP 14-fold less potent than native SP. The N-terminal peptide (NP) was inactive by itself but inhibited CP-elicited behavior. Naloxone antagonized this action of NP and shifted the SPF dose-response curve 4-fold to the left. However, naloxone had no effect on the action of CP or on the action of any of the native neurokinins. The results are consistent with the hypothesis that N- and C-terminal analogs of SP can have opioid and SP-like actions, respectively, in the CNS of rodents. Furthermore, analogs of SP which include at least the terminal tetrapeptide retain neurokinin activity.

The crystal structure of a bimorphinan with highly selective kappa opioid receptor antagonist activity

Abstract The crystal structure of the dihydrobromide heptahydrate of nor-binaltorphimine (17, 17′-bis(cyclopropylmethyl)-6,6′,7,7′-tetrahydro-4,5α: 4′,5′α-diepoxy-6,6′-imino[7,7′ bimorphinan]-3,3′,14,14′-tetraol)is presented. This structure is the first reported structure of a rigid bivalent opioid ligand. Two morphinan pharmacophores are connected by a rigid spacer, the pyrrole ring. The nor-binaltorphimine structure itself shows unique, high selectivity as a kappa opioid receptor antagonist. Crystal data: P 3 2 , Z = 3, a = b = 20.223 (4), c = 9.541(7) A, α = β = 90°, γ = 120°; R = 0.079 (1765 reflections, F obs > 1σ( F )).

Transfer of fatty acyl groups from membrane phosphatides to opiate ligands

Investigation of the persistent opioid receptor binding of hydrazine-containing opiate ligands to brain membranes has revealed that it is related to conversion of these ligands to fatty acylhydrazone or fatty acylhydrazide derivatives. The fatty acyl group was found to be derived from membrane phosphatides. Persistent binding does not occur when this pool of phosphatides is removed by extensive washing, and it is restored upon addition of phosphatide to the membranes. In washed membranes, synthetically derived fatty acylhydrazones exhibited persistent binding similar to that found when naltrexonazine was incubated with brain membranes. It is suggested that the persistent binding is a consequence of the localization of fatty acylnaltrexazone derived from naltrexonazine in a membrane lipid bilayer that interfaces with the opioid receptor system rather than the persistence of naltrexonazine itself.