STEREOISOMERS OF [H-3] N-ALLYLNORMETAZOCINE BIND TO DIFFERENT SITES IN MOUSE-BRAIN

  • 1 January 1984
    • journal article
    • research article
    • Vol. 231  (3) , 539-544
Abstract
(+)- and (-)-[3H]-N-allylnormetazocine (NANM) were synthesized and evaluated for binding to mouse brain membranes. Scatchard analysis of the saturable binding of (-)-[3H]NANM suggested a single class of binding sites with an apparent Kd of 2.1 nM and an estimated maximum binding of 197 fmol/mg of protein. Increasing the concentration of Na+, K+, Mn2+ or Ca2+ decreased (-)-[3H]NANM specific binding. (-)-[3H]NANM apparently binds to the .mu.-opiate receptor in that (-)-isomers, but not the (+)-isomers, of N-cis-3-chloroallylnormetazocine, N-propynylnormetazocine, pentazocine, cyclazocine, naloxone, phenazocine and morphine competed for binding. (-)-Isomers of ethylketocyclazocine, ketocyclazocine and NIH 9101 [ (-)-5,9-dimethyl-2''-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan] also displaced (-)-[3H]NANM binding which suggested .kappa. activity in addition to .mu. activity. Phencyclidine and its analogs did not bind to the (-)-[3H]NANM site. Scatchard analysis of saturable binding of (+)-[3H]NANM also revealed a homogenous population of binding sites with apparent Kd of 12 nM and an estimated maximum binding of 360 fmol/mg of protein. This binding site was unaffected by increasing concentrations of Na+ and K+, but binding was decreased by high concentrations of Mn2+ and Ca2+. The (+)-isomers of the benzomorphans N-cis-3-chloroallylnormetazocine, phenazocine, pentazocine and cyclazocine effectively displaced (+)-[3H]NANM binding. The (+)-isomers of ketocyclazocine and ethylketocyclazocine, as well as dextrorphan, a (+)-morphinan, bind to the (+)-[3H]NANM site. The (-)-isomers of .mu. agonist/antagonists and .kappa. agonists competed poorly, or not at all, for the (+)-[3H]NANM site, whereas phencyclidine and related compounds exhibited a low affinity for this site. The isomers of NANM bind to 2 distinct sites in mouse brain membranes suggesting a heterogeneity of actions of the putative .sigma. agonist (.+-.)-NANM.