A Comparison of the inhibitory effects of aromatic substituted benzhydryl ethers on the uptake of catecholamines and serotonin into synaptosomal preparations of the rat brain

Zee, P. van der; Hespe, W.

doi:10.1016/0028-3908(78)90054-0

Cited by 8 publications

(8 citation statements)

References 29 publications

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“…All of the 4'-substituted or 4',4"-disubstituted 3a-(diphenylmethoxy)tropane analogs were evaluated for inhibition of [3H]dopamine uptake in rat caudate putamen, Table 3. Compounds 7a-c have been previously reported as dopamine uptake inhibitors.19 20 All of the compounds that bound with high affinity to the dopamine transporter were potent inhibitors of dopamine uptake. This was evidenced by the high, significant correlation (r = 0.907; p < 0.0001) between log A values for binding and log IC50 values for inhibiting dopamine uptake, Figure 2.…”

Section: Resultsmentioning

confidence: 98%

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Novel 4'-Substituted and 4',4''-Disubstituted 3.alpha.-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors

et al. 1995

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A series of 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter. These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters. All of these compounds monophasically displaced [3H]WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM. The most potent compound in this series was 4',4"-difluoro 3 alpha-(diphenylmethoxy)tropane 7c with a Ki = 11.8 nM. All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter. None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM) transporters. Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter. Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake. The present data coupled with the observed differences from cocaine in structure-activity relationships suggested that the 3 alpha-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.

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Section: Resultsmentioning

confidence: 98%

“…Representative spectral data of 7a: 1H NMR (300 MHz, CDCI3) <5 1.82-1.89 (m, 4H, H-2,4ax,eq), 1.94-1.97 (m, 2H, H-6,7exo), 2.08-2.12 (m, 2H, H-6,7endo), 2.24 (s, 3H, N-CHa), 3.07 (br t, 2H, H-1,5), 3.54 (t, J = 4.6 Hz, 1H, H-3eq), 5.37 Cl at 343), 235 (10), 201 (15), 165 (20), 140 (100, base), 124…”

Section: Methodsmentioning

confidence: 99%

Novel 4'-Substituted and 4',4''-Disubstituted 3.alpha.-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors

et al. 1995

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“…Benztropine (3α-(diphenylmethoxy)-1α H ,5α H -tropane) is the parent compound in a class of dopamine uptake inhibitors. − This compound is equipotent to cocaine at the dopamine transporter and has been shown to be a central nervous system (CNS) stimulant in animal models. − Benztropine is interesting in that it shares some structural homology with cocaine (and numerous analogs of cocaine, e.g., WIN 35,428) as well as the 1,4-dialky(en)ylpiperazine compounds (e.g., GBR 12909). Previous reports from this laboratory 12,13 demonstrated the effects of various para aromatic substitutions on the structure−activity relationships of benztropine at the dopamine transporter.…”

Section: Introductionmentioning

confidence: 99%

3‘-Chloro-3α-(diphenylmethoxy)tropane But Not 4‘-Chloro-3α- (diphenylmethoxy)tropane Produces a Cocaine-like Behavioral Profile

et al. 1997

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A series of 2'- and 3'-substituted and 3',3"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (Ki). Generally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported para-substituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K1 = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.

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“…The benzhydryl ether moiety is abundant in a number of naturally occurring and biologically active compounds as well as molecules of potential clinical use and also exhibit various pharmacological potentials. In addition such molecules possess properties such as non-nucleoside reverse transcriptase inhibition (Brahmachari, 2010), anti-plasmodial and antitrypanosomal action (Weis et al, 2006), monoamine uptake inhibition, anti-depressant and anti-Parkinsonian activity (Van Der Zee & Hespe, 1978;Nilsson et al, 1969), and anti-histaminic (McGavack et al, 1948) and anti-spasmodic (Loew & Kaiser, 1945) action. Naturally occurring symmetrical bis(benzhydryl)ethers are also known to show promising therapeutic potential including significant anti-platelet aggregation efficacy (Pyo et al, 2004).…”

Section: S1 Commentmentioning

confidence: 99%

1,1′,1′′,1′′′-(Oxydimethanetriyl)tetrakis(4-fluorobenzene)

Roopashree

Kavitha²,

Katagi

et al. 2014

Acta Cryst E

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A Comparison of the inhibitory effects of aromatic substituted benzhydryl ethers on the uptake of catecholamines and serotonin into synaptosomal preparations of the rat brain

Cited by 8 publications

References 29 publications

Novel 4'-Substituted and 4',4''-Disubstituted 3.alpha.-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors

Novel 4'-Substituted and 4',4''-Disubstituted 3.alpha.-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors

3‘-Chloro-3α-(diphenylmethoxy)tropane But Not 4‘-Chloro-3α- (diphenylmethoxy)tropane Produces a Cocaine-like Behavioral Profile

1,1′,1′′,1′′′-(Oxydimethanetriyl)tetrakis(4-fluorobenzene)

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