A NEW INHIBITOR OF NOREPINEPHRINE UPTAKE DEVOID OF AFFINITY FOR RECEPTORS IN RAT-BRAIN

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 222  (1) , 61-65
Abstract
LY135252, (.+-.)-N-methyl-.gamma.-(2-methylphenoxy)phenylpropylamine hydrochloride, is a competitive inhibitor of norepinephrine [NE] uptake in synaptosomes of rat hypothalamus. The resolved optical (-)-isomer, LY139603, is 2 and 9 times more effective than the racemate and the (+)-isomer, LY139602, with inhibitor constants (Ki) of 1.9, 3,4 and 16.8 nM, respectively. All 3 compounds are relatively weak in the inhibition of dopamine and serotonin uptake, with Ki values at least 2 orders of magnitude greater. The racemate and the 2 optical isomers in vivo are potent inhibitors of NE uptake with relative effectiveness being parallel with their K1 values. The most potent and long-acting compound was the (-)-isomer, LY139603, which inhibited NE uptake ex vivo with an ED50 value of 2.2 mg/kg i.p. and a half-life of 6.4 h. In comparison with the tricyclic antidepressants desipramine and imipramine, LY139603 is a relatively weak ligand for .alpha.-1, .alpha.-2 and .beta.-adrenergic receptors, acetylcholine-muscarinic receptors, histaminergic H1 receptors and the receptors of GABA and benzodiazepines. LY139603 is a remarkably specific inhibitor of NE uptake. Its potential as an antidepressant is discussed.