Pharmacological Properties of 403U76, a New Chemical Class of 5-Hydroxytryptamine- and Noradrenaline-reuptake Inhibitor

Abstract

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.

Pharmacological Characterization ofN,N-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

“…To date, few radiotracers have had optimal properties to allow in vivo study of the serotonin transporter, due mainly to high in vivo nonspecific binding or inappropriate kinetics. Derivative compounds from the diphenyl sulfide structure (Ferris et al, 1995) have recently been proposed as potent tracers for scintigraphic exploration of the serotonin transporter, in particular iodo-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol (Oya et al, 1999), ADAM Acton et al, 2001), and DASB (Ginovart et al, 2001). Our team recently described the synthesis and evaluation of several new compounds from this chemical family (Emond et al, 2002); among these derivatives, MADAM appeared to be a good candidate because of its high selective binding to the serotonin transporter compared with dopamine and norepinephrine transporters.…”

“…The cocaine derivatives ␤-CIT (Brü cke et al, 1993;Malison et al, 1998) and nor-␤-CIT (Hiltunen et al, 1998) have been used for SPET studies, but neither is selective as they also bind to dopamine transporters. Several derivatives from another chemical family such as 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol or 403U76 (Ferris et al, 1995), iodo-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol (Oya et al, 1999), and 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine benzyl alcohol or ADAM , have recently been described as potent ligands of serotonin transporters. ADAM seems to be the best tracer among these compounds in terms of affinity, selectivity, and in vivo properties for SPET exploration of the serotonin transporter .…”

Synthesis and in vitro evaluation of new diphenyl ether derivatives as serotonin transporter ligands

“…The combined organic phases were washed with brine, dried over Na 2 SO 4 , and then the solvent was removed under reduced pressure. The obtained yellow oil was purified by flash column (iv) N- (6). To a stirred solution of 4 (0.79 g, 2.3 mmol) in dry CH 2 Cl 2 (10 mL), a mixture of ethyl formate (121 mmol, 10 mL) and dry CH 2 Cl 2 (5 mL) was added dropwise at 0 .…”

“…In recent years, a new series of selective SERT ligands have been investigated based on the structure of the diphenylsulfide 403U76 ( Figure 1) [6] . Several SPECT radiotracers, such as [ 123 I]IDAM [7] , [ 123 I]ODAM [8] , [ 123 I] ADAM [9] , and two [ 123 I]-labeled oxygen and methylene bridged derivatives of ADAM [10] have been developed.…”

“…Several SPECT radiotracers, such as [ 123 I]IDAM [7] , [ 123 I]ODAM [8] , [ 123 I] ADAM [9] , and two [ 123 I]-labeled oxygen and methylene bridged derivatives of ADAM [10] have been developed. Various PET radiotracers like [ 11 C]DASB [11] , [ 11 C] DAPP, [ 11 C]MADAM [12] , [ 11 C]DAPA [13] , [ 11 C]AFA [14] , [ 11 C]EADAM [15] , [ 11 C]AFE [16] , [ 11 C]AFM [17] , [ 11 C] HOMADAM [18] , [ 11 C]SMe-ADAM [19] , [ 18 F]ACF [20] , [4-18 F]-ADAM [21,22] , [5][6][7][8][9][10][11][12][13][14][15][16][17][18] F]-ADAM [23] , [ [24] have been described. All these compounds show high potential in binding to the SERT, with moderate to high signal-to-noise ratios and different brain kinetics in vivo.…”