Structure-Activity Relationships at the Monoamine Transporters for a Novel Series of Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) Analogues

Abstract

A series of modafinil (1) analogues was synthesized wherein 1) para-halo-substitutents were added to the aryl rings, 2) the sulfoxide function was removed, and 3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on DAT, SERT and NET binding. In addition, the locomotor-stimulant effects in mice of (±)-modafinil (1), its R- and S-enantiomers and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine.

Figure 1

Racemic modafinil and its enantiomers.

Scheme 1. Synthesis of Modafinil Analogues

Reagents and conditions: (a) Thioglycolic acid (1 equiv), TFA, room temperature, overnight. (b) i) CH₃I, K₂CO₃, acetone, reflux, 4 h; (ii) NH₄OH, NH₄Cl, MeOH, 50 °C, 72 h. (c) H₂O₂ (30%), AcOH:MeOH (1:3), 40 °C, 24 h.

Scheme 2. Synthesis of Modafinil Analogues

Reagents and conditions: (a) (i) CDI, THF, room temperature, 2 h; (ii) HNRR′, THF, room temperature, overnight. (b) H₂O₂ (30%), AcOH:MeOH (1:3), 40 °C, 24 h. (c) LiAlH₄, H₂SO₄, THF.

Figure 2

Dose-dependent effects of (±)-1, its enantiomers R-1 and S-1, and 5c on locomotor activity in mice. Ordinates: horizontal locomotor activity counts after drug administration in counts per min. Abscissae: dose of drug in mg/kg, log scale. Each point represents the average effect determined in six mice. The data are from the 30 min period at the start of each of 4 h after drug administration. Note that neither (±)-modafinil, its enantiomers, or the analogue produced a maximal stimulation of activity that was equivalent to that of cocaine and that compound 5c only had effects in the third and fourth hour after its administration at the highest dose tested.