Synthesis, Cocaine Receptor Affinity, and Dopamine Uptake Inhibition of Several New 2.beta.-Substituted 3.beta.-Phenyltropanes

Kelkar, S. V.; Izenwasser, Sari; Katz, Jonathan L.; Klein, Cheryl L.; Zhu, Naijue; Trudell, Mark L.

doi:10.1021/jm00049a004

Cited by 35 publications

(62 citation statements)

References 9 publications

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“…[65][66][67][68][69][70][71] Subsequently, a wide variety of alkyl, alkenyl, and arylalkyl substituents were placed in the 2-position resulting in highly potent dopamine uptake inhibitors. [72][73][74][75][76] In fact, classical structure-activity relationships, QSAR and CoMFA studies, all supported the promiscuity of this position for binding at the DAT, and thus it has provided an ideal place to add radiolabels, photoaffinity labels, and other bulky substituents, without compromising binding potency. The only requirement for most of these substituents is that the stereochemistry at the 2-position must be b, and the stereochemistry must be R(À)-in order to provide optimal binding at DAT.…”

Section: B Cocaine and The 3-aryl Tropanesmentioning

confidence: 93%

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Newman

Kulkarni

2002

Medicinal Research Reviews

107

144

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In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics.

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Section: B Cocaine and The 3-aryl Tropanesmentioning

confidence: 93%

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Newman

Kulkarni

2002

Medicinal Research Reviews

107

144

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“…The focus of much attention in the design of prospective medications for cocaine abuse has been the class of bicyclo [3.2.1]octanes. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] This focus has its historic origins in the structure of cocaine itself ( Figure 1) as well as the metabolically more stable lead tropane, WIN 35,428, a 3β-aryl-2β-carbomethoxy-8-azabicyclo[3.2.1]octane analogue of cocaine disclosed by Clarke et al in 1973. 24 Until 1997 when we presented evidence 14 that the 8-aza functionality within the bicyclo [3.2.1] octane (tropane) series is not a prerequisite for potent inhibition of monoamine uptake systems, it was assumed that the presence of an amine nitrogen was essential for binding to these systems.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters

Pham-Huu

Deschamps

Liu

et al. 2007

Bioorganic & Medicinal Chemistry

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Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3beta-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC(50)=5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC(50)=4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3alpha-aryl analogues (2-fold), but more robust (>10-fold) for the 3beta-aryl analogues. The (1R)-configuration provided the eutomers.

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“…The methylated nitrogen atom mimics that of acetylcholine and thereby leads to inhibition of muscarinic acetylcholine receptors (Schmeller et al, 1995). Binding to dopamine receptors is mediated by the stereochemistry of substituents at the C-2 and C-3 positions (Carroll et al, 1992a;Kelkar et al, 1994), with the strongest affinity being found for compounds containing an aromatic ring connected directly or indirectly to the 3b position (Carroll et al, 1992b). This in turn explains why cocaine exhibits both anesthetic and euphorigenic properties.…”

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confidence: 99%

The Last Step in Cocaine Biosynthesis Is Catalyzed by a BAHD Acyltransferase

et al. 2014

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ORCID IDs: 0000-0003-1007-4700 (J.J.); 0000-0002-4865-3938 (J.C.D.).The esterification of methylecgonine (2-carbomethoxy-3b-tropine) with benzoic acid is the final step in the biosynthetic pathway leading to the production of cocaine in Erythoxylum coca. Here we report the identification of a member of the BAHD family of plant acyltransferases as cocaine synthase. The enzyme is capable of producing both cocaine and cinnamoylcocaine via the activated benzoyl-or cinnamoyl-Coenzyme A thioesters, respectively. Cocaine synthase activity is highest in young developing leaves, especially in the palisade parenchyma and spongy mesophyll. These data correlate well with the tissue distribution pattern of cocaine as visualized with antibodies. Matrix-assisted laser-desorption ionization mass spectral imaging revealed that cocaine and cinnamoylcocaine are differently distributed on the upper versus lower leaf surfaces. Our findings provide further evidence that tropane alkaloid biosynthesis in the Erythroxylaceae occurs in the above-ground portions of the plant in contrast with the Solanaceae, in which tropane alkaloid biosynthesis occurs in the roots.

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Synthesis, Cocaine Receptor Affinity, and Dopamine Uptake Inhibition of Several New 2.beta.-Substituted 3.beta.-Phenyltropanes

Cited by 35 publications

References 9 publications

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters

The Last Step in Cocaine Biosynthesis Is Catalyzed by a BAHD Acyltransferase

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