Synthesis of dopamine transporter selective 3-{2-(Diarylmethoxyethylidene)}-8-alkylaryl-8-azabicyclo[3.2.1]octanes

Bradley, Amy L.; Izenwasser, Sari; Wade, Dean; Cararas, Shaine; Trudell, Mark L.

doi:10.1016/s0960-894x(02)01051-x

Cited by 11 publications

(11 citation statements)

References 21 publications

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“…This compound had a K i of 52 nM. The Nphenylpropyl analog D17 possessed a K i of 19 nM in one report [81] and 7.4 nM in another report [82]. The N-benzyl analog D16 had a K i of 5.7 nM [82].…”

Section: Benztropinesmentioning

confidence: 97%

“…The Nphenylpropyl analog D17 possessed a K i of 19 nM in one report [81] and 7.4 nM in another report [82]. The N-benzyl analog D16 had a K i of 5.7 nM [82]. Compound D18, which has a double bond methylene linker between the tropane ring and the benzhydryl ether, has a K i of 19 nM [81].…”

Section: Benztropinesmentioning

confidence: 98%

“…Compound D18, which has a double bond methylene linker between the tropane ring and the benzhydryl ether, has a K i of 19 nM [81]. The Nbenzyl and N-phenylpropyl analogs D19 and D20 had K i s of 7.9 and 3.7 nM, respectively [82].…”

Section: Benztropinesmentioning

confidence: 99%

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Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

Sp¹,

Fi²

2006

CTMC

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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.

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Section: Benztropinesmentioning

confidence: 97%

Section: Benztropinesmentioning

confidence: 98%

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Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

Sp¹,

Fi²

2006

CTMC

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“…26 Previous efforts in our laboratories have identified a novel class of GBR-related 8-alkylaryl-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives that exhibit potent and selective affinity for the DAT. 39,40 These preliminary in vitro studies demonstrated GBR-analogues 7 – 12 exhibited GBR-like affinity at the DAT but were up to 300-fold more selective for the DAT over the SERT. 38,39 The potent and highly selective pharmacological profile of these 8-alkylaryl-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives has prompted further investigation of the SAR of this novel class of DAT ligands in search of potent highly selective ligands.…”

Section: Introductionmentioning

confidence: 92%

“…5 and 6 ) scaffolds. 25,26,38,39 These studies have led to the development of a well-defined pharmacophore for high affinity and selectivity. 26 Previous efforts in our laboratories have identified a novel class of GBR-related 8-alkylaryl-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives that exhibit potent and selective affinity for the DAT.…”

Section: Introductionmentioning

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

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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).

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