Synthesis and Biological Evaluation of Bupropion Analogues as Potential Pharmacotherapies for Smoking Cessation

Abstract

Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human α3β4*, α4β2, α4β4, and α1* nAChRs. The analogues were evaluated for their ability to block nicotine-induced effects in four tests in mice. Nine analogues showed increased monoamine uptake inhibition. Similar to 2a all but one analogue show inhibition of nAChR function selective for human α3β4*-nAChR. Nine analogues have higher affinity at α3β4*-nAChRs than 2a. Four analogues also had higher affinity for α4β2 nAChR. Analogues 2r, 2m, and 2n with AD 50 values of 0.014, 0.015, and 0.028 mg/kg were 87, 81, and 43 times more potent than 2a in blocking nicotine-induced antinociception in the tail-flick test. Analogue 2x with IC 50 values of 31 and 180 nM for DA and NE, respectively, and IC 50 = 0.62 and 9.8 μm for antagonism of α3β4 and α4β2 nAChRs had the best overall in vitro profile relative to 2a.

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

“…Although four stereoisomers are expected, only two trans-diastereomers, SS-and RR-OHBUP, were detected in plasma and when synthesized de novo (Suckow et al, 1997;Carroll et al, 2010Carroll et al, , 2014. These data are consistent with the suggestion that steric hindrance reduces cyclization to the cis-diastereomers, (2R,3S)-and (2S,3R)-OHBUP, and favors the thermodynamically more stable trans-isomers .…”

Interaction of nicotinic receptors with bupropion: Structural, functional, and pre-clinical perspectives

“…The pharmacological activities [i.e., inhibitory potency (Table 1) and binding affinities (Table 2)] of BP, its natural metabolites, as well as (±)-SADU-3-72, a photoreactive BP derivative (Figure 1) for different AChR subtypes have been studied by in vitro approaches. In addition, functional studies have shown that BP and its analogs inhibit both muscle-and neuronal-type AChRs in the low to intermediate micromolar range [2,20] . The BP selectivity for different AChRs follows the sequence: 3-> 4-~ 1-> 7-containing AChRs (Table 1).…”

“…Moreover, BP induces locomotor stimulation, although this activity is mild [16][17][18] . BP has also been found to decrease not only nicotine but also the addictive and craving effects elicited by methamphetamine in humans [19] , and by cocaine in rodents [20] , as well as morphine-induced tolerance and dependence in rodents [21] .…”

An Overview on the N-Heterocyclic Carbene-Catalyzed Aza-Benzoin Condensation Reaction

“…In the benzoin-type condensation reaction, after the nucleophilic attack of the cyanide catalyst on the acylsilane, the mechanism involves a [1,2] shift of the migrating SiR3 group (Brook rearrangement), generating the key stabilized acyl anion equivalent, in analogy with the Breslow catalytic cycle.…”

“…α-Amino ketones are widespread structural moieties, common to both natural and synthetic significant compounds in medicinal chemistry ( Figure 1) [1][2][3][4]. They are largely employed as building blocks in the preparation of a large number of molecules, in particular, 1,2-aminoalcohols, and vicinal diamines (Scheme 1).…”