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

Abstract

Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S)-hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at α3β4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a-5h as possibly superior candidates as aids to smoking cessation.

Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence

“…Blocking the pronounced release of DA by methamphetamine may therefore be an interesting therapeutic option for the treatment of methamphetamine dependence [1]. Bupropion and methylphenidate are DA uptake inhibitors that interact with the same pharmacological target as methamphetamine [6-11]. Bupropion is used as an antidepressant and smoking cessation aid [7,9].…”

“…Methamphetamine also releases norepinephrine [2,3] and norepinephrine is thought to contribute to the acute effects of amphetamine-type drugs [3,37-39]. MDPV [25] and methylphenidate [6,40], and to a lower extent bupropion [7,11], block the norepinephrine transporter and these drugs could also block methamphetamine-induced norepinephrine release. We did not address potential drug interactions at the norepinephrine transporter because in contrast to DA, norepinephrine is not generally thought to be a major mediator of the addictive properties of psychostimulants.…”

Cadmium Increases the Sensitivity of Adolescent Female Mice to Nicotine-Related Behavioral Deficits

“…An increase in metabolism induced by nicotine is often associated with an increased motor function [ 41 ]. A model that addresses such function is linked with the ability of nicotine to stimulate nicotine receptors at the neuromuscular junctions and increase the release of epinephrine [ 42 , 43 ]. As a result, glucose uptake increases in the muscles, thereby facilitating an increase in motor function [ 44 ].…”

(±)-2-(N-tert-Butylamino)-3′-[125I]-iodo-4′-azidopropiophenone: A dopamine transporter and nicotinic acetylcholine receptor photoaffinity ligand based on bupropion (Wellbutrin, Zyban)

“…3 Given its clinical versatility, a number of analogs of (±)- 1 and its major active metabolite, (2 S ,3 S )-hydroxybupropion, have been recently disclosed in the search for improved pharmacotherapies for smoking cessation and cocaine addiction. 4-7 Despite these well-documented therapeutic effects, the neurochemical mechanisms underlying bupropion’s action are still not well-defined, and the molecular determinants of how (±)- 1 interacts with its major drug targets remain unknown.…”

“…Slight adjustments to the nAChR activity of an analog with a NDRI profile may be the key to developing more efficacious smoking cessation aids. 7 …”