Effect of ring-constrained phenylpropyloxyethylamines on sigma receptors

Abstract

A series of ring-constrained phenylpropyloxyethylamines, partial opioid structure analogs and derivatives of a previously studied sigma (σ) receptor ligand, was synthesized and evaluated at σ and opioid receptors for receptor selectivity. The results of this study identified several compounds with nanomolar affinity at both σ receptor subtypes. Compounds 6 and 9 had the highest selectivity for both σ receptor subtypes, compared to μ opioid receptors. In addition, compounds 6 and 9 significantly reduced the convulsive effects of cocaine in mice, which would be consistent with antagonism of σ receptors.

Keywords: Antagonists; Opioid; Phenylpropyloxyethylaminesl; Sigma.

Figure 1.

Cocaine-induced convulsions. (A) Pretreatment of Swiss Webster mice with compound 6 (0–30 mg/kg ip), followed by a convulsive dose of cocaine (70 mg/kg ip) produced a reduction in the convulsive effects of cocaine. (B) Pretreatment of Swiss Webster mice with compound 9 (0–10 mg/kg ip), followed by a convulsive dose of cocaine (70 mg/kg ip) produced a dose-dependent reduction in the convulsive effects of cocaine. *p < 0.05; **p < 0.01; Fisher’s exact test.

Scheme 1.

Synthesis of 3, 4 6, 7, 9 and 10. Reagents and conditions: A, (a) HCHO, HCOOH, reflux; (b) cinnamyl bromide or 1-bromo-3-phenylpropane, NaH, DMF. 50 °C, 3 h. B, (c) N-methyl-phenethylamine, EtOH, reflux; (d) 1-bromo-3-phenylpropane, NaH, DMF, 50 °C, 3 h; (e) 3-phenylpropylamine, EtOH, reflux; (f) HCHO, HCOOH, reflux; (g) 1-bromo-3-phenylpropane, NaH, DMF, 50 °C.