CoMFA Study of Novel Phenyl Ring-Substituted 3α-(Diphenylmethoxy)tropane Analogues at the Dopamine Transporter

Newman, Amy Hauck; Izenwasser, Sari; Robarge, Michael J.; Kline, Richard H.

doi:10.1021/jm980701v

Cited by 31 publications

(41 citation statements)

References 33 publications

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“…36 This study further confirmed structure-activity relationships, but also demonstrated that the steric interaction of these compounds was the most prominent component to predict DAT binding affinities. 36 These studies also provided early support for the differences in structure-activity relationships between these tropane-based dopamine uptake inhibitors and the 3-aryl tropane or cocaine series of compounds.…”

Section: Structure-activity Relationships At Datsupporting

confidence: 69%

“…CoMFA studies have been conducted on the 3-position of the tropane ring for both the cocaine and 3-aryl tropane class of compounds 82,83,87 and the benztropines. 36 The 3D-QSAR studies lend further support for distinctive structure-activity relationships at this position and differing binding interactions at the DAT between these two classes of compounds. CoMFA studies performed on cocaine and the 3-aryl tropane analogues suggested that the steric component is a predominant factor in their binding affinities, with electrostatics playing a smaller, yet significant role.…”

Section: B Cocaine and The 3-aryl Tropanesmentioning

confidence: 73%

“…However, in both series of compounds optimal binding affinities at the DAT were achieved with the 4 0 ,4 00 -diF-subsitituted diphenyl ether or diphenylamine. 30,36,39 Modifications of the propyl linker between the piperazine ring and the diphenyl ether have also been made with success. 117,121,122 These modifications have suggested that the role of the oxygen in the diphenyl ether is simply as a spacer atom and can be replaced with nitrogen or a methylene group.…”

Section: Gbr 12909 and Its Analoguesmentioning

confidence: 99%

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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

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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: Structure-activity Relationships At Datsupporting

confidence: 69%

Section: B Cocaine and The 3-aryl Tropanesmentioning

confidence: 73%

Section: Gbr 12909 and Its Analoguesmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

107

144

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“…To test this hypothesis, we have used a library of 3-phenyltropane analogs and substituted amphetamines to examine structural components of these compounds that are critical for recognition by hSERT, dSERT, and the H The results of these assays were used as input for modeling using CoMFA. CoMFA has proven valuable in previous studies as a method to model protein-ligand interactions in systems that lack protein crystal structures or other definitive structural information (Carroll et al, 1994;Wilcox et al, 1998;Li et al, 1999;Newman et al, 1999). The six models presented here indicate differences in recognition on four levels.…”

mentioning

confidence: 91%

Distinct Molecular Recognition of Psychostimulants by Human andDrosophilaSerotonin Transporters

Roman¹,

Saldaña²,

Nichols³

et al. 2003

J Pharmacol Exp Ther

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In this study, human embryonic kidney (HEK)-293 cells stably expressing human, Drosophila, or a chimeric serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, dSERT, , respectively) were used to explore the ability of two libraries of structurally distinct psychostimulants to inhibit 5-HT uptake. One library consisted of 3-phenyltropane analogs, whereas the second library consisted of several substituted amphetamines. hSERT exhibited a lower K i value for all the compounds in both libraries compared with dSERT, whereas the chimeric SERT exhibited properties more closely resembling those of dSERT. This species selectivity was explored using computer-generated comparative molecular field analysis to model the interactions of the cocaine analogs and substituted amphetamines at hSERT, dSERT, and the crossspecies chimera. Models for the 3-phenyltropane analogs indicate that a region exists around the aromatic ring where decreased electron density is favored, particularly for hSERT. This finding may indicate pi-pi stacking with an aromatic amino acid residue in SERT. Also, electronegative substituents in the 4Ј-position provide favorable interactions. This structural feature was demonstrated by increased potency of analogs with electronegative substituents on the aromatic ring that withdraw electron density. For the substituted amphetamines, key areas for interaction exist around the amine, an electrostatic component surrounding the 3-position on the aromatic ring, and a steric component surrounding the 4-position.

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“…25 The histamine H 1 -pharmacophore was then used for superimposition of the BZT analogs. The quality of the superimpositions was evaluated based on the RMSD values and the ΔVs as defined earlier.…”

Section: Molecular Modelingmentioning

confidence: 99%

Comparative structure–activity relationships of benztropine analogues at the dopamine transporter and histamine H1 receptors

Kulkarni¹,

Kopajtic²,

Katz³

et al. 2006

Bioorganic & Medicinal Chemistry

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Benztropine (BZT) and its analogues inhibit dopamine uptake and bind with moderate to high affinity to the dopamine transporter (DAT). However, many of these compounds, in contrast to other monoamine uptake inhibitors, lack cocaine-like behavioral effects and fail to potentiate the effects of cocaine. The BZT analogues also exhibit varied binding affinities for muscarinic M 1 and histamine H 1 receptors. In this study a comparative analysis was conducted of pharmacophoric features with respect to the activities of BZT analogues at the DAT and at the histamine H 1 receptor. The BZT analogues showed a wide range of histamine H 1 receptor (Ki =16-37600 nM) and DAT (Ki=8.5-6370 nM) binding affinities. A stereoselective histamine H 1 -antagonist pharmacophore, using a five-point superimposition of classical antagonists on the template, cyproheptadine, was developed. A series of superimpositions and comparisons were performed with various analogues of BZT. In general, smaller substituents were well tolerated on the aromatic rings of the diphenyl methoxy group for both the DAT and H 1 receptor, however for the H 1 receptor, substitution at only one of the aromatic rings was preferred. The substituents at the 2-and N-positions of the tropane ring were preferred for DAT however these groups seem to overlap receptor essential regions in the histamine H 1 receptor. Molecular models at the DAT and the histamine H 1 receptor provide further insight into the structural requirements for binding affinity and selectivity that can be implemented in future drug design.

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CoMFA Study of Novel Phenyl Ring-Substituted 3α-(Diphenylmethoxy)tropane Analogues at the Dopamine Transporter

Cited by 31 publications

References 33 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

Distinct Molecular Recognition of Psychostimulants by Human andDrosophilaSerotonin Transporters

Comparative structure–activity relationships of benztropine analogues at the dopamine transporter and histamine H1 receptors

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