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MPTP-3-ol injected s.c. once daily for 4 days resulted in a dose-dependent depletion of striatal dopamine and cortical norepinephrine one week after the last dose. MPTP-3-ol was approximately one-fourth as potent as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in causing these effects. MPTP-3-ol was oxidized by monoamine oxidase in mouse brain in vitro and resulted in MPP+ (1-methyl-4-phenylpyridinium) formation in brain in vivo, both at about one-fourth the rates with MPTP. The in vitro metabolism of MPTP-3-ol was inhibited by deprenyl, a selective inhibitor of monoamine oxidase type B, and deprenyl pretreatment also blocked the depletion of striatal dopamine and cortical norepinephrine in vivo. Pretreatment with EXP 561, an inhibitor of catecholamine uptake, also prevented the dopamine- and norepinephrine-depleting effects of MPTP-3-ol. Thus, substitution of a hydroxy group on the 3-position of MPTP retains its neurotoxic potential toward catecholamine neurons but reduces potency by decreasing the rate of oxidation via monoamine oxidase type B.

LY227942, (+/-)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thiophene)propanamine ethanedioate, is a new, competitive inhibitor of monoamine uptake in synaptosomal preparations of rat brain. LY227942 inhibits uptake of serotonin (5-hydroxytryptamine, 5HT) and norepinephrine (NE) in cortical synaptosomes and uptake of dopamine (DA) in striatal synaptosomes with inhibitor constants (Ki values) of 8.5, 45 and 300 nM, respectively. Upon administration in vivo, LY227942 lowers 5HT and NE uptake in hypothalamus homogenates to half their respective control activities (ED50) at 0.74 and 1.2 mg/kg s.c., 7 and 12 mg/kg i.p., and 12 and 22 mg/kg p.o., but LY227942 at doses up to 30 mg/kg p.o. does not change DA uptake in striatal homogenates. Lowering of 5HT and NE uptake is demonstrated after 15 min and 6 hr, but has dissipated by 16 hr after oral administration. According to radioligand binding determinations, LY227942 possesses only weak affinity for muscarinic receptors, histamine-1 receptors, adrenergic receptors, dopamine receptors and serotonin receptors. These findings suggest that LY227942 has the pharmacological profile of an antidepressant drug and is useful to study the pharmacological responses of concerted enhancement of serotonergic and noradrenergic neurotransmission.