Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogs of 3,4-(methylenedioxy)amphetamine

Abstract

Benzofuran, indan and tetrahydronaphthalene analogs of 3,4-(methylenedioxy)amphetamine (MDA) were prepared in order to examine the role of the dioxole ring oxygen atoms of MDA in interacting with the serotonin and catecholamine uptake carriers. The series of compounds was evaluated for discriminative stimulus effects in rats trained to discriminate saline from the training drugs (S)-(+)-MBDB (1c), MMAI (3), and (S)-(+)-amphetamine and for the ability to inhibit the uptake of [3H]serotonin, [3H]dopamine, and [3H]norepinephrine into crude synaptosome preparations. Behaviorally, the benzofuran and indan analogs 4-6 produced similar discriminative cues, whereas the tetralin derivative 7 did not fully substitute for the training drugs. The results in the in vitro pharmacology studies indicate that selectivity for 5-HT versus catecholamine uptake carriers may be modulated by the position and orientation of ring oxygen atoms. However, the nonoxygenated isostere 6 possessed high potency at all uptake sites examined. Enlargement of the saturated ring by one methylene unit to give the tetralin derivative resulted in a large (3-4-fold) reduction in activity at catecholamine sites.

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine

“…These studies are the first to evaluate the discriminative stimulus and locomotor effects of 5-APB and expand on previous investigations into the discriminative stimulus effects of 6-APDB (Monte et al, 1993). Both 6-APDB and 5-APB produce robust and long-lasting locomotor stimulation with roughly equal potency in a manner similar to cocaine, methamphetamine, and several synthetic cathinones (Gatch et al, 2013); however, these benzofurans demonstrate a delayed onset of effects relative to other psychostimulants.…”

“…The discriminative stimulus of 5-APB differs slightly from 6-APDB in that 5-APB produces a greater level methamphetamine-appropriate responding (77%) than 6-APDB (33%), hinting at a potentially greater dopaminergic component of the discriminative stimulus of 5-APB relative to 6-APDB. In vitro characterizations of the benzofurans ’ mechanisms have indicated an MDMA-like mechanism, in that both compounds are potent monoamine-releasing agents with a greater relative selectivity for SERT over DAT (Rickli et al, 2015b; Monte et al, 1993). Furthermore, both benzofurans are agonists at the 5-HT 2 receptor subtypes, which likely underlies their partial substitution for DOM (Rickli et al, 2015b).…”

“…All four compounds, MDMA, flephedrone, MDAI, and DMAA produced dose-dependent depressant effects followed by weak rebound stimulant effects (Gatch et al, 2013; 2016). However, MDMA and MDAI have mixed serotonergic and dopaminergic pharmacology, and DMAA produces its effects primarily through adrenergic receptors (Monte et al, 1993; Iversen et al, 2014). Given the structural and behavioral similarities between flephedrone and 4-FA and their departure from the locomotor and discriminative stimulus of traditional stimulant-like drugs, para -fluorination appears to confer unique effects to amphetamine-like compounds.…”

“…Benzofuran analogs of amphetamine (benzofurans) were initially synthesized as part of investigation into structure-activity relations of ring-substituted amphetamines (Monte et al, 1993). The derivatives 5- and 6-(2-aminpropyl)-benzofuran (5- and 6-APB) and 5- and 6-(2-aminopropyl)-2,3-dihydrobenzofuran (5- and 6-APDB) were commonly used in Benzofury formulations, which could readily be purchased online prior to scheduling (Jebadurai et al, 2013).…”

Synthese von neuen (Phenylalkyl)aminen zur Untersuchung von Struktur–Aktivitätsbeziehungen. Mitteilung 2

“…Die chromatographische Reinigung lieferte schliesslich reines 9e in 32% Ausbeute. Vielleicht kˆnnte durch das Verwenden von Dichloromethyl-methylether und SnCl 4 in CH 2 Cl 2 [22] anstelle der Vilsmeier-Bedingungen eine hˆhere Regioselektivit‰t zugunsten 9e erzielt werden, was jedoch nicht untersucht wurde.…”