Behavioral And Neurochemical Effects of Amphetamine Analogs That Release Monoamines in the Squirrel Monkey

To date, there are no effective pharmacotherapies for treating psychostimulant abuse. Previous preclinical and clinical studies have shown that continuous treatment with the monoamine releaser amphetamine reduces cocaine self-administration, but amphetamine selectively targets the dopamine system and is reinforcing. In the present study, we examined the consequences of administration of amphetamine and three structurally related analogs that vary in their potencies for releasing dopamine and serotonin on behavioral-stimulant effects and nucleusaccumbens dopamine levels in squirrel monkeys. Amphetamine and PAL-353, which have relatively high selectivity for releasing dopamine vs. serotonin, increased accumbens dopamine levels and induced stimulant effects on behavior maintained by a fixed-interval schedule of reinforcement. PAL-313, which has a relatively low selectivity for releasing dopamine vs. serotonin, increased dopamine levels, but did not induce behavioral-stimulant effects. PAL-287, which is relatively nonselective in releasing dopamine and serotonin, did not increase dopamine levels or induce behavioral-stimulant effects. These results demonstrate that increasing serotonergic activity attenuates dopamine release and dopamine-mediated behavioral effects of monoamine releasers. In addition, these results support further investigation of PAL-313 and similar compounds as a potential medication for treating psychostimulant abuse

Synthesis And Biological Evaluation Of Bupropion Analogues As Potential Pharmacotherapies For Smoking Cessation

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 IC50 values of 31 and 180 nM for DA and NE, respectively, and with IC50 of 0.62 and 9.8 μm for antagonism of α3β4 and α4β2 nAChRs had the best overall in vitro profile relative to 2a. © 2010 American Chemical Society

Nicotinic Acetylcholine Receptor Efficacy And Pharmacological Properties Of 3-(Substituted Phenyl)-2β-Substituted Tropanes

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. © 2010 American Chemical Society

Synthesis Of 2-(Substituted Phenyl)-355-Trimethylmorpholine Analogues And Their Effects On Monoamine Uptake Nicotinic Acetylcholine Receptor Function And Behavioral Effects Of Nicotine

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. © 2011 American Chemical Society

Synthesis And Characterization Of In Vitro And In Vivo Profiles Of Hydroxybupropion Analogues: Aids To Smoking Cessation

To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropions possible mechanisms of action(s), 23 analogues based on its active hydroxymetabolite (2S,3S)-4a were synthesized and tested for their abilities to inhibit monoamine uptake and nAChR subtype activities in vitro and acute effects of nicotine in vivo. The 3′,4′-dichlorophenyl [(±)-4n], naphthyl (4r), and 3-chlorophenyl or 3-propyl analogues 4s and 4t, respectively, had higher inhibitory potency and/or absolute selectivity than (2S,3S)-4a for inhibition of DA, NE, or 5HT uptake. The 3′-fluorophenyl, 3′-bromophenyl, and 4-biphenyl analogues 4c, 4d, and 4l, respectively, had higher potency for antagonism of α4β2-nAChR than (2S,3S)-4a. Several analogues also had higher potency than (2S,3S)-4a as antagonists of nicotine-mediated antinociception in the tail-flick assay. The results suggest that compounds acting via some combination of DA, NE, or 5HT inhibition and/or antagonism of α4β2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence. © 2010 American Chemical Society

The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users

Development of norepinephrine transporter reuptake inhibition assays using SK-N-BE(2)C cells

This report describes efforts to develop and validate novel norepinephrine transporter reuptake inhibition assays using human neuroblastoma SK-N-BE(2)C cells in 24-well format. Before conducting the assays, the SK-N-BE(2)C cells were first evaluated for their ability to uptake [3H]norepinephrine and were shown to have a saturable uptake with a KM value of 416 nM. Using this determined KM value, reuptake inhibition assays were then conducted with a variety of ligands including antidepressants, as well as piperazine and phenyltropane derivatives. The results obtained with the SK-N-BE(2)C cells indicate that this model system can detect a range of ligand potencies, which compare well with other established transporter assays. Our data suggest that SK-N-BE(2)C cells have potential utility to serve as another model system to detect norepinephrine reuptake inhibition activity