Properties of 8,9-dichloro-2,3,4,5-tetrahydro-1H- 2-benzazepine, an inhibitor of norepinephrine N-methyltransferase

Abstract

LY134046, 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride, was a potent inhibitor of norepinephrine N-methyltransferase (NMT) from rat brain or rabbit adrenal glands in vitro. The inhibition was competitive with respect to the methyl-accepting substrate, (-)-norepinephrine, the K i for LY134046 being 2.4 × 10 −8 M. LY134046 inhibited the NMT activity in rat brain stem and hypothalamus in vivo at doses of 10–40 mg/kg, i.p., and lowered the epinephrine (but not norepinephrine or dopamine) concentration in these brain regions. The epinephrine reduction produced by a single 40 mg/kg, i.p. dose of LY134046 persisted at 24 hr and daily injections of 10–40 mg/kg doses for 5 days produced cumulative reductions in epinephrine concentration. LY134046 was similar to SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride), a structurally related compound, as an inhibitor of NMT in vitro and in vivo, but the two compounds differed in their relative abilities to block α 2 receptors. SK&F 64139 was 20-to 50-fold more potent than LY134046 in antagonizing [ 3H]clonidine binding to rat brain membranes and phenylephrine-induced contractions of rat aortic strips, but it was only about twice as potent as LY134046 in inhibiting NMT activity. LY134046 seems to be more selective than other currently known inhibitors of NMT and may be useful for pharmacologic intervention in the function of epinephrine-forming neurons in brain.