Nicotinic Acetylcholine Receptor Efficacy and Pharmacological Properties of 3-(Substituted phenyl)-2β-substituted Tropanes

Abstract

There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of α3β4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.

Synthesis of 2-(Substituted Phenyl)-3,5,5-trimethylmorpholine Analogues and Their Effects on Monoamine Uptake, Nicotinic Acetylcholine Receptor Function, and Behavioral Effects of Nicotine

“…In our previous studies, 8,[11][12][13] we succeeded in generating analogues with reasonably higher inhibitory potency than 2 or either of its hydroxymetabolite isomers (R,R)-4a and (S,S)-4a in both the in vitro and In Vivo assays used in this study, whether on the 2, hydroxybupropion, or 3-phenyltropane backbones. 8,12,13 The current studies show that several 3,5,5-morpholino analogues 5a-5h also have higher potency than 2, (R,R)-4a, and (S,S)-4a in the same test.…”

“…Dose-response curves were determined using a minimum of four different doses of test compound, and at least eight mice were used per dose group. IA = AD 50 > 20 mg/kg. b NT = not tested. c Taken from reference 13. …”

“…Several of these agents have superior activities relative to 2 or its active metabolite ( S,S )- 4a as inhibitors of DA or NE uptake or of nAChR function and have very promising in vivo profiles as inhibitors of nicotine-induced dependence behaviors 8,11–13…”

“…Our earlier work toward a goal of developing superior aids to smoking cessation concerned analogues of 2, its (S,S)-or (R,R)hydroxymetabolites (S,S)-4a or (R,R)-4a, respectively, or 3-phenyltropane-related compounds. 8,[11][12][13] Several of these agents have superior activities relative to 2 or its active metabolite (S,S)-4a as inhibitors of DA or NE uptake or of nAChR function and have very promising In Vivo profiles as inhibitors of nicotineinduced dependence behaviors. 8,[11][12][13] To explore potential utility as smoking cessation aids of compounds having related structural topology and to define possible mechanism(s) of action of these compounds, we now describe the synthesis and in vitro and In Vivo effects of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h.…”

“…8,[11][12][13] Several of these agents have superior activities relative to 2 or its active metabolite (S,S)-4a as inhibitors of DA or NE uptake or of nAChR function and have very promising In Vivo profiles as inhibitors of nicotineinduced dependence behaviors. 8,[11][12][13] To explore potential utility as smoking cessation aids of compounds having related structural topology and to define possible mechanism(s) of action of these compounds, we now describe the synthesis and in vitro and In Vivo effects of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h. Compounds (S,S)-and (R,R)-5a are analogues of the hydroxybupropion metabolites (S,S)-and (R,R)-4a, where the hydroxy group has been replaced by a hydrogen.…”