Structure−Activity Relationship Studies of Novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine Analogs:  Synthesis and Biological Evaluation at the Dopamine and Serotonin Transporter Sites

Dutta, Aloke K.; Xu, Cen; Reith, Maarten E. A.

doi:10.1021/jm9506581

Cited by 57 publications

(73 citation statements)

References 43 publications

(101 reference statements)

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“…In contrast, for (ϩ)-2-carbomethoxy-benztropine compounds, replacement of the tropane nitrogen with an oxygen markedly reduced DAT-binding affinity (Meltzer et al, 1997), complementing our findings that the benztropine compounds also require a basic nitrogen for high-affinity binding to DAT (Agoston et al, 1997a). Although a non-nitrogenous analog of GBR 12909 has not been reported, it has been found that one but not the other terminal piperazine nitrogen could be replaced with a methine group without significant diminution of DAT-binding affinity (Dutta et al, 1993(Dutta et al, , 1996. The required nitrogen on which the propylphenyl side chain is attached is analogous to the tropane nitrogen in our benztropine series.…”

Section: Discussionsupporting

confidence: 83%

Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter

et al. 1999

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Benztropine and its analogs are tropane ring-containing dopamine uptake inhibitors that produce behavioral effects markedly different from cocaine and other dopamine transporter blockers. We investigated the benztropine binding site on dopamine transporters by covalently attaching a benztropine-based photoaffinity ligand, 125 I]RTI 82 occurs closer to the C terminal in a domain containing transmembrane helices 4-7. Thus, although benztropine and cocaine both contain tropane rings, their binding sites are distinct, suggesting that dopamine transport inhibition may occur by different mechanisms. These results support previously derived structure-activity relationships suggesting that benztropine and cocaine analogs bind to different domains on the dopamine transporter. These differing molecular interactions may lead to the distinctive behavioral profiles of these compounds in animal models of drug abuse and indicate promise for the development of benztropine-based molecules for cocaine substitution therapies.

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Section: Discussionsupporting

confidence: 83%

Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter

et al. 1999

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“…110 Expansion of the piperidine analogue series has led to some potent DAT ligands that show some divergence from the structure-activity relationships derived from the piperazinyl GBR 12909 analogues. [112][113][114] In particular, the terminal N-benzyl-piperidine analogue is equipotent to GBR 12909, whereas the N-benzyl analogue of GBR 12909 is 17-fold less potent in inhibiting dopamine uptake than the parent drug. Interestingly, the 3,4-dichloro-substituted benzyl piperidine analogue displayed lower affinity at DAT, but significant selectivity over SERT.…”

Section: Gbr 12909 and Its Analoguesmentioning

confidence: 99%

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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“…3,[12][13][14][15][16] In our initial series of rimcazole analogues, the most potent DAT inhibitor, 1 (K i ) 61 nM), showed moderately potent σ 1 binding affinity (K i ) 97 nM) and was ∼3-fold less potent at SERT (K i ) 219 nM) and 60-fold selective over NET. 11 Several rimcazole analogues (1-4) were evaluated in animal models of cocaine abuse and toxicity.…”

Section: Introductionmentioning

confidence: 99%

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

et al. 2003

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Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i ) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)-amine analogues have now been prepared in which the most potent DAT compound, 19 (K i ) 8.5 nM), was selective over serotonin transporter (SERT/DAT ) 94), norepinephrine transporter (NET/DAT ) 63), and σ 1 receptor binding (σ 1 /DAT ) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i ) 77 and 124 nM, respectively, 17; K i ) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.

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Structure−Activity Relationship Studies of Novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine Analogs: Synthesis and Biological Evaluation at the Dopamine and Serotonin Transporter Sites

Cited by 57 publications

References 43 publications

Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter

Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter

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

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

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Structure−Activity Relationship Studies of Novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine Analogs: Synthesis and Biological Evaluation at the Dopamine and Serotonin Transporter Sites

Cited by 57 publications

References 43 publications

Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter

Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter

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

Dual Probes for the Dopamine Transporter and σ1 Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

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Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents