Synthesis and ligand binding of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter. Simultaneous measurement of serotonin and paroxetine in rat brain microdialysate by a single-pump column-switching technique. Inhibition of 5-HT cell firing in the DRN by non-selective 5-HT reuptake inhibitors: studies on the role of 5-HT1A autoreceptors and noradrenergic mechanisms. Rx drugs

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J Med Chem. 1997 Apr 25;40(9):1366-72.
Synthesis and ligand binding of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter.

Emond P, Garreau L, Chalon S, Boazi M, Caillet M, Bricard J, Frangin Y, Mauclaire L, Besnard JC, Guilloteau D.

INSERM U316, Laboratoire de Biophysique Medicale et Pharmaceutique, Tours, France.

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9135033&dopt=Abstract

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J Chromatogr B Biomed Sci Appl. 1997 Mar 28;691(1):119-29.
Simultaneous measurement of serotonin and paroxetine in rat brain microdialysate by a single-pump column-switching technique.

Ramaiya A, Karnes HT.

Department of Pharmacy and Pharmaceutics, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-980533, USA.

Simultaneous quantitation of paroxetine and serotonin in rat brain microdialysate is presented as a means to study the neuropharmacokinetics and neuropharmacodynamics of paroxetine, a selective serotonin reuptake inhibitor. In order to achieve this objective, a single-pump column-switching technique was developed. Optimization of the mobile phase in terms of the concentration of ion-pairing agent, pH of mobile phase, temperature of the stationary phase and concentration of organic modifier was investigated and a single mobile phase was developed for both separations. The design was such that the switching valve employed column I (50 mm length) and column II (250 mm length) in series in position A. At 15.3 min, the valve was switched to position B, in which the flow of the mobile phase was directed only through the short column (column I). A flow gradient program was used to increase the flow-rate from 0.125 ml/min to 0.4 ml/min, which enabled a reduction in total analysis time to less than 20 min. The limits of detection for serotonin and paroxetine were 6 fmol and 300 fmol, respectively. The accuracy of the method demonstrated percent differences from spiked samples that were within 12.5% and the precision was found to be within 10% R.S.D.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140765&dopt=Abstract

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Psychopharmacology (Berl). 1997 Apr;130(3):261-8.
Inhibition of 5-HT cell firing in the DRN by non-selective 5-HT reuptake inhibitors: studies on the role of 5-HT1A autoreceptors and noradrenergic mechanisms.

Gartside SE, Umbers V, Sharp T.

University of Oxford, Department of Clinical Pharmacology, Radcliffe Infirmary, UK.

Improved clinical antidepressant efficacy may result if the acute inhibition of 5-HT cell firing induced by antidepressants is prevented. Here we examined whether inhibition of 5-HT cell firing by non-selective 5-HT uptake inhibiting antidepressant drugs is reversed by a selective 5-HT1A receptor antagonist. In addition, we examined whether concomitant blockade of NA uptake offsets the inhibition of 5-HT cell firing resulting from 5-HT uptake blockade. Antidepressants which block 5-HT uptake (paroxetine, clomipramine, amitriptyline, venlafaxine), all caused dose-dependent and complete inhibition of 5-HT cell firing. Desipramine, a selective NA uptake blocker, caused a slight reduction in firing. The selective 5-HT1A receptor antagonist, WAY 100635, reversed the inhibition of 5-HT cell firing induced by clomipramine, amitriptyline, venlafaxine, and paroxetine, but not that induced by the alpha 1 adrenoceptor antagonist, prazosin. Desipramine, at a dose which increased extracellular NA in the DRN, reversed the effect of prazosin but did not alter the ability of paroxetine to inhibit 5-HT cell firing. Our data indicate that antidepressant drugs with 5-HT uptake blocking properties inhibit 5-HT cell firing via activation of 5-HT1A autoreceptors, and do so irrespective of their effects on NA uptake. These data are discussed in relation to the application of 5-HT1A receptor antagonists to enhance the clinical efficacy of antidepressant drugs.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9151361&dopt=Abstract

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