Isomer effects on uptake

Isomer effects on metabolism Isomer effects on uptake Isomer effects on excretion Practical considerations A Racemates or enantiomers ... 

Based on the modest ability of the (+)-isomers of MDMA and MBDB to inhibit the reuptake of norepinephrine (NE) into hypothalamic synaptosomes (Steele et al. 1987). it seemed possible that noradrenergic pathways might be involved in the eue. In ano er series of drug discrimination experiments designed to test this hypothesis, the specific NE uptake inhibitor (-)-tomoxctine was tested for stimulus transfer in doses up to 10 mg/kg in MDMA-trained rats. At 5 mg/kg, 67 percent of the animals responded on, the drug lever. However, pretreatment with tomoxetine in six rats trained to discriminate MDMA from saline had no effect on the discrimination of a subsequent dose of MDMA. 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

This has two detrimental effects on polymerization. First, chelation strengthens the metal-olefin interaction, thereby raising the barrier for the insertion step. Second, it forces insertion through the endo face, in sharp contrast to the known propensity for norbornene to insert into metal-carbon bonds through the less hindered exo face [3 a, 5]. Consistent with this hypothesis has been our observation of the preferential uptake of the exo isomer in the polymerization of functional norbornene derivatives by Pd(PRj)(Me). For example. Fig. 9.3 shows the uptake profile versus time for the polymerization of 5-norbornene-2-carboxyhc acid ethyl ester starting with a monomer isomer ratio of 22% exo to 78% endo. Indeed, under certain conditions a polymer can be obtained from the exo isomer but not the endo isomer [10]. 

The selective inhibition of NA uptake by viloxazine, in the absence of effects on DA or 5-HT uptake, resided in the trans-S-isomer, paralleling the reserpine reversal effects.81 The anorectic drug mazindol was also a potent inhibitor of NA uptake,82 like its structural relative ciclazindol (22).83 In a double-blind trial, 2 was as effective as amitriptyline in ameliorating endogenous depression. Ciclazindol, which lacked significant anticholinergic or cardiotoxic effects, produced fewer side-effects than amitriptyline. Diverse structures included befuraline (DIV 154, 23) an... 

RU 25591 (3), also a potent serotonin uptake inhibitor, suppresses food intake in dogs, rats and pigs. The trans isomer has no effect on food intake in dogs. Tolerance to the anorexigenic activity of RU 25591 developed during a two-week course of treatment. The duration of action for the appetite suppression is shorter than that observed for the inhibition of serotonin uptake, suggesting the involvement of other pathways in its mechanism of action. 

Under this heading also (64) should be mentioned, which was the most active in its series in inhibiting 5-HT uptake by human platelets (in vitro). It antagonized the effects of reserpine, but NA-uptake inhibiting in vitro data were not mentioned. The unsubstituted and the para fluoro isomer of (64) were also active [167]. With the -NHMe analogue BW 247 (65) a study of the effect on the EEC of healthy persons has been reported [168]. 

In several antidepressant tests, (46) is very active the oral EDso in reserpine and tetrabenazine tests is 03-1 mg kg" [133,134]. Compound (46), and also its meta-MeO analogue, with 5biogenic amine uptake mechanisms in mouse and rat heart were half as potent as, and of shorter duration than, those of imipramine (I). Uptake of NA in rat medulla or hypothalamus was not inhibited by (46), but alteration of the NA-metabolite pattern was similar to that associated with (I) [136]. Ginically a rapid onset of action of (46) in depressed patients was claimed [ 137], but in subsequent trials only a minority adhered to this view in general no difference from imipramine was demonstrated in various double-blind trials [132]. It appeared to have less peripheral anticholinergic and possibly a lower intrinsic activity in blocking the monoamine uptake process than (1). In depressed patients with clear anxiety components, (46) showed also favourable results [138]. 

Their mechanism of lowering tissue levels of norepinephrine is not related to an interference of the uptake, storage or release of catecholamines. The administration of 05-MI results in a depletion of norepinephrine in various tissues of animals and a reduction in the synthesis of catecholamines by 70 percent in man. Although only the 1-isomer of OS-MI is active as a tyrosine hydroxylase inhibitor, the d-form potentiates the action of OS-MT, a phenomenon which has been postulated to occur as a result of an effect on membrane permeability. a-MI has served as a valuable experimental tool wherever the involvement of catecholamines has... 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

Baba, A., Yamamoto, T., Yamamoto, H., Suzuki, T., and Moroji, T., Effects of the major metabolite of phencyclidine, the trans isomer of 4-phenyl-4-(l-piperidinyl) cyclohexanol, on [3H]N-(l-[2-thie-nyl]cyclohexyl)-3,4-piperidine([3H TPC) binding and [3H] dopamine uptake in the rat brain, Neurosci. Lett., 182, 119, 1994. 

Girvin et al. [358] evaluated the release of PCBs from electrical substation soils contaminated with transformer fluids. They observed that there are two phases to the uptake and release of PCBs with these soils. The initial phase is a rapid, labile phase that is followed by a slower, nonlabile phase. The labile phase occurs at a scale of hours to days while the nonlabile phase releases over weeks and months. Girvin et al. [422] also reviewed the effects of adsorption on the mobility of PCBs and their transport. In an example presented for a hexa-chlorobiphenyl, these authors noted that the PCB isomer would have a retardation factor Rf of 1400 for the particular case given. This means that the ground-... 

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