Structure–activity studies of 3′-4′-dichloro-meperidine analogues at dopamine and serotonin transporters

Rhoden, Jill B.; Bouvet, M A; Izenwasser, Sari; Wade, Dean; Lomenzo, Stacey A.; Trudell, Mark L.

doi:10.1016/j.bmc.2005.05.025

Cited by 12 publications

(10 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Binding affinities for the dopamine, serotonin and norepinephrine transporters were determined by the ability of the drug to displace the radiolabeled ligands [ 3 H]WIN 35,428, [ 3 H]citalopram, and [ 3 H]nisoxetine, respectively, from the monoamine transporters obtained from rat brain tissue using previously reported assays. 40, 43,44 The binding affinities of all compounds listed in Table 1 were initially determined for the DAT. The compounds that exhibited DAT binding affinities with K i values < 100 nM were evaluated at the serotonin and norepinephrine transporters to determine transporter selectivity.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Further structure–activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

Cararas

Izenwasser

Wade

et al. 2011

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

The synthesis and structure-activity relationships of 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives were investigated at the dopamine transporter(DAT), the serotonin transporter (SERT) and norepinephrine transporter (NET). The rigid ethylidenyl-8-azabicyclic[3.2.1]octane skeleton imparted modestly stereoselective binding and uptake inhibition at the DAT. Additional structure-activity studies provided a transporter affinity profile that was reminiscent of the structure-activity of GBR 12909. From these studies, the 8-cyclopropylmethyl group has been identified as a unique moiety that imparts high SERT/DAT selectivity. In this study the 8-cyclopropylmethyl derivative 22e (DAT Ki of 4.0 nM) was among the most potent compounds of the series at the DAT and was the most DAT selective ligand of the series (SERT/DAT:1060). Similarly, the 8-chlorobenzyl derivative 22g (DAT Ki of 3.9 nM) was found to be highly selective for the DAT over the NET (NET/DAT: 1358).

show abstract

Section: Resultsmentioning

confidence: 99%

“…In fact the greater than 1000-fold SERT/DAT selectivity observed for 22e is among the highest reported for any DAT ligand. 28–30, 44 In addition, 22e was also selective for DAT over NET (NET/DAT: 625) albeit less than the SERT.…”

Section: Resultsmentioning

confidence: 99%

Further structure–activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

Cararas

Izenwasser

Wade

et al. 2011

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this review we have highlighted the most potent and selective molecules from each structural class; however, several other unique structures have been identified that possess either moderate affinity and or moderate selectivity for the DAT. Rhoden and colleagues prepared meperidine derivatives (E19) having altered N-and ester substituents [94]. Krunic and co-workers studied a series of 3-aryl substituted trop-2-enes (E20) [95].…”

Section: D29mentioning

confidence: 99%

Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

Sp¹,

Fi²

2006

CTMC

View full text Add to dashboard Cite

The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as well as normal aging. Considerable effort continues to be devoted to the development of new ligands for the DAT. In this review, we present some of the more interesting ligands developed during the last few years from the 3-phenytropane, 1,4-dialkylpiperazine, phenylpiperidine, and benztropine classes of DAT uptake inhibitors as well as a few less studied miscellaneous DAT uptake inhibitors. Studies related to the therapeutic potential of some of the more studied compounds are presented. A few of the compounds have been studied as pharmacotherapies for Parkinson's disease, ADHD, and obesity. However, most of the drug discovery studies have been directed toward pharmacotherapies for stimulant abuse (mainly cocaine). A number of the compounds showed decreased cocaine maintained responding in rhesus monkeys trained to self-administer cocaine. One compound, GBR 12,909, was evaluated in a Phase 1 clinical trial.

show abstract

“…20-23 Previously, we have reported on a series of derivatives of meperidine ( 1 ) that exhibited modest potency and selectivity for the SERT (Figure 2). 21,22 However, unlike the prototypical SSRIs fluoxetine and paroxetine, the meperidine analogues 2 lack a secondary amine and two aromatic moieties common to the SERT pharmacophore. 24,25 In light of these deficiencies it was of interest to examine this class of meperidine-based SERT ligands to determine if SERT potency could be improved and the monoamine transporter selectivity influenced by the addition of a second strategically placed aryl ring system.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structure–activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands

Izenwasser

Wade

et al. 2010

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

A series of benzyl esters of meperidine and normeperidine were synthesized and evaluated for binding affinity at serotonin, dopamine and norepinephrine transporters. The 4-methoxybenzyl ester 8b and 4-nitrobenzyl ester 8c in the meperidine series and 4-methoxybenzyl ester 14a in the normeperidine series exhibited low nanomolar binding affinities at the SERT (Ki values < 2 nM) and high SERT selectivity (DAT/SERT >1500 and NET/SERT > 1500).

show abstract

Structure–activity studies of 3′-4′-dichloro-meperidine analogues at dopamine and serotonin transporters

Cited by 12 publications

References 27 publications

Further structure–activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

Further structure–activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

Synthesis and structure–activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands

Contact Info

Product

Resources

About