benzofurans and talsupram

PET and SPECT ligands for the norepinephrine transporter (NET) will be important tools for studying the physiology, pathophysiology and pharmacology of the CNS noradrenergic system in vivo. A series of candidate NET ligands were synthesized and characterized in terms of their affinity for human monoamine transporters. The two most promising compounds, talopram and talsupram, were radiolabeled with carbon-11 and evaluated through biodistribution studies in rats and PET imaging studies in a rhesus monkey. Although both compounds displayed high affinity and selectivity for the human NET in vitro, these compounds did not enter the CNS in adequate amounts to be used in PET imaging studies.

Topics: Alkylation; Animals; Benzofurans; Binding, Competitive; Chromatography, High Pressure Liquid; Dopamine Plasma Membrane Transport Proteins; Indicators and Reagents; Ligands; Macaca mulatta; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Norepinephrine Plasma Membrane Transport Proteins; Positron-Emission Tomography; Propylamines; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Spectrophotometry, Ultraviolet; Stereoisomerism; Symporters; Thiophenes; Tissue Distribution

The rat forced swim test (FST) is a model that is used extensively as a screening test for antidepressant activity. It has previously been reported that thorough analysis of behaviour in this model reveals two distinct types of active response - climbing and swimming - and that these are separately evoked by re-uptake inhibitors selective for noradrenaline (NA) and serotonin (5-HT), respectively. In the present study, utilising re-uptake inhibitors selective for NA, talsupram, and 5-HT, 5-chloro-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)- phthalan (Lu 10-134-C), we examined if this scoring technique could detect the antidepressant potential of a selective serotonin re-uptake inhibitor (SSRI), and whether re-uptake inhibitors selective for distinct monoamine systems induce exclusive behavioural responses. We also analysed if chronic antidepressant administration for three weeks was more effective than acute treatment. We found Lu 10-134-C (40 mg/kg; PO) to be behaviourally active in this paradigm. Although treatment with talsupram (40 mg/kg; PO) resulted solely in climbing behaviour, Lu 10-134-C induced both climbing and swimming behaviour. However, chronic pre-treatment with either re-uptake inhibitor (20 mg/kg; twice daily; PO) failed to augment the response observed with acute treatment. Similarly, chronic administration of either compound was without effect on the basal, or stress-induced, serum corticosterone concentrations or anterior pituitary (AP) preproopiomelanocorticotropin (POMC) mRNA expression. These results suggest that selective monoamine re-uptake inhibition produces distinct, but not necessarily exclusive, behavioural responses in the forced swim test.

Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; Behavior, Animal; Benzofurans; Butylamines; Corticosterone; Drug Administration Schedule; Drug Evaluation, Preclinical; Escape Reaction; Hypokinesia; Male; Pituitary Gland, Anterior; Pro-Opiomelanocortin; Rats; Rats, Wistar; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Sensitivity and Specificity; Swimming; Thiophenes

Topics: Animals; Antidepressive Agents; Benzofurans; Desipramine; Hypothalamus; In Vitro Techniques; Kinetics; Male; Myocardial Contraction; Norepinephrine; Rabbits; Rats; Stereoisomerism; Structure-Activity Relationship; Sympathetic Nervous System; Synaptosomes; Thiophenes

Topics: Animals; Benzofurans; Catecholamines; Dibenzocycloheptenes; Drug Synergism; Epinephrine; Female; Methylamines; Phenoxybenzamine; Pupil; Rabbits; Thiophenes; Time Factors