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:10.1002/chin.200325161

Cited by 4 publications

(6 citation statements)

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“…[24][25][26][27] In addition, the diarylmethoxy group has been established as an important structural feature of the DAT selective ligand GBR 12909 and related GBR/ tropane hybrid analogues. [28][29][30][31][32][33] Therefore, it was of interest to investigate the effects of the diarylmethoxy group at the 2-position for a series of 3β-aryltropanes. Herein, we describe the synthesis, DAT, serotonin (SERT), norepinephrine transporter (NET), and muscarinic M 1 receptor binding affinities for a series of 2-(diarylmethoxyalkyl)-3β-aryltropanes.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives

Kulkarni

Izenwasser

et al. 2004

J. Med. Chem.

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3 beta-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively, the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor selectivity over SERT. These SAR studies provide further evidence for the varied binding requirements of structurally diverse tropane-based ligands and support future studies to elucidate DAT binding requirements in relation to cocaine-like behavioral endpoints.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives

Kulkarni

Izenwasser

et al. 2004

J. Med. Chem.

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“…1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.12 (q, J=7. 20 Hz, 2 H), 3.09 (br s, 2 H), 2.46-2.42 (m, 1 H), 2.45 (d, J = 8.40 Hz, 2 H), 2.24 (s, 3 H), 2.15-2.10 (m, 2 H), 2.07-2.02 (m, 2 H), 1.64 (m, 2 H), 1.31-1.21 (m, 2 H), 1.24 (t, J = 7.20 Hz, 3 H).…”

Section: Methodsmentioning

confidence: 99%

“…Tropinone 2a was converted to the corresponding R,β unsaturated ester 3a via a Horner-Wadsworth-Emmons (HWE) reaction with trimethyl phosphonacetate. [18][19][20] Catalytic hydrogenation of 3a gave the C-3 endo isomer 4a as the main product. 19,21 Alternatively, the Knoevenagel condensation of 2a with ethyl cyanoacetate gave an intermediate alkene, 22 which was hydrogenated to afford the saturated nitrile derivative 3b.…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis, and Structure−Activity Relationship of Tropane Muscarinic Acetylcholine Receptor Antagonists

et al. 2009

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Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.

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“…17 In this regard, central piperazine ring-constrained GBR 12909 derivatives and modified GBR structures based on the tropane moiety have also been developed recently. [18][19][20] One of our research goals is to explore possible bioactive conformations of our molecules interacting with the DAT. In this effort, and to expand our SAR studies further in the search for suitable pharmacotherapeutic agents for cocaine addiction, the design of more structurally constrained molecules of 3,6-disubstituted derivative was undertaken.…”

Section: Introductionmentioning

confidence: 99%

Further Structurally Constrained Analogues of cis-(6-Benzhydrylpiperidin-3-yl)benzylamine with Elucidation of Bioactive Conformation: Discovery of 1,4-Diazabicyclo[3.3.1]nonane Derivatives and Evaluation of Their Biological Properties for the Monoamine Transporters

et al. 2004

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Our structure-activity relationship (SAR) study on piperidine analogues for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, structurally constrained versions of flexible piperidine analogues, with preferential affinity for the dopamine transporter (DAT). In our attempt to further rigidify this structure to study influence of rigidity on binding and in vivo activity, we have developed a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. All synthesized derivatives were tested for their affinity at the DAT, serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [(3)H]WIN 35, 428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also tested for their ability to inhibit uptake of [(3)H]DA. The SAR study led to the discovery of a potent lead compound (-)-S,S-10c which exhibited high affinity and selectivity for the DAT (IC(50) = 22.5 nM; SERT/DAT = 384 and NET/DAT > 444). It is interesting to note that both (-)-10c and the lead compound from the 3,6-disubstituted series (-)-2 exhibited highest activity in their (S,S) isomer indicating similar requirement of regiospecificity for maximum interaction. Overall, our current SAR results corresponded well with the results from less constrained 3,6-disubstituted versions of these molecules albeit the former class exhibited more stringent requirement in molecular structure for activity. However, the potent compounds in the current series exhibited greater selectivity for the DAT compared to their corresponding lesser constrained 3,6-disubstituted versions indicating an effect of rigidity in selective interaction with the transporter proteins. In an effort to elucidate the bioactive conformational structure of the lead molecules in the current and the 3,6-disubstituted series, a preliminary molecular modeling study was carried out where the most rigid derivative (-)-10c was used as a template structure. Compounds (-)-2 and (-)-10c exhibited stimulant activity in locomotor tests in mice in which (-)-2 exhibited a slower onset and longer duration of action compared to (-)-10c. Both compounds occasioned complete cocaine-like responding in mice trained to discriminate 10 mg/kg ip cocaine from vehicle.

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Synthesis of Dopamine Transporter Selective 3‐{2‐(Diarylmethoxyethylidene)}‐8‐alkylaryl‐8‐azabicyclo[3.2.1]octanes.

Cited by 4 publications

References 1 publication

Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives

Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives

Design, Synthesis, and Structure−Activity Relationship of Tropane Muscarinic Acetylcholine Receptor Antagonists

Further Structurally Constrained Analogues of cis-(6-Benzhydrylpiperidin-3-yl)benzylamine with Elucidation of Bioactive Conformation: Discovery of 1,4-Diazabicyclo[3.3.1]nonane Derivatives and Evaluation of Their Biological Properties for the Monoamine Transporters

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