Serotonin synthesis inhibitor

Serotonin Receptors Presynaptic Drug Effects 4.5.3.1 Serotonin Synthesis Inhibitors... 

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

The initial hydroxylation of tryptophan, rather than the decarboxylation of 5-HTP, appears to be the rate-limiting step in serotonin synthesis. Therefore, the inhibition of this reaction results in a marked depletion of the content of 5-HT in brain. The enzyme inhibitor most widely used in experiments is parachlorophenylalanine (PCPA). In vivo, PCPA irreversibly inhibits tryptophan hydroxylase, presumably by incorporating itself into the enzyme to produce an inactive protein. This results in a long-lasting reduction of 5-HT levels. Recovery of enzyme activity, and 5-HT biosynthesis, requires the synthesis of new enzyme. Marked increases in mRNA for tryptophan hydroxylase are found in the raphe nuclei 1-3 days after administration of PCPA [6]. 

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). 

Paroxetine hydrochloride is a selective serotonin reuptake inhibitor that is used as an antidepressant. The chemoenzymatic synthesis can be carried out... 

Synthesis inhibitors block tryptophan hydroxylase, the first rate-determining enzyme in serotonin synthesis. Although p-chlorophenylalanine (4.111) can decrease serotonin levels by more than 90%, this agent does not cause the sedation that is seen after catecholamine depletion with reserpine. Therefore, reserpine, although capable of depleting 5-HT vesicles, causes sedation by a catecholaminergic mechanism that inhibits uptake-2. It acts on the membrane of the synaptic vesicle and seems to prevent 5-HT and catecholamine uptake into the granule. 

Linezolid Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit Bacteriostatic activity against susceptible bacteria Infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci Oral, IV hepatic clearance (half-life 6 h) dosed twice-daily Toxicity Duration-dependent bone marrow suppression, neuropathy, and optic neuritis serotonin-syndrome may occur when coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors)... 

Serotonin is synthesized via tryptophan and 5-hydroxytryptophan with decarboxylation of the latter (Fig. 25-12). Within the pineal body of the brain and in the retina, serotonin is acetylated to N-acetylseroto-nin,782/783 which is then O-methylated to melatonin, the pineal hormone (Fig. 25-12). A specific inhibitor of serotonin synthesis is p-chlorophenylalanine, and studies with this and other inhibitors suggest that serotonin is required for sleep.784... 

Beak used this method in a synthesis of (-)-paroxetine 97 (Paxil or Seroxat), a selective serotonin reuptake inhibitor.9 Lithiation of 92 with n-BuLi-(-)-sparteine and addition of the product 93 to the nitroalkene 94 yields the protected Z-enamine 95, as usual for reactions of lithiated allylamides, in >94% ee. Hydrolysis and reduction of the product, followed by mesylation and cyclisation gave the fnms-substituted piperidine 96. Displacement of the hydroxyl group by sesamol yielded (-)-paroxetine 97. 

According to the authors tetrahydrobiopterin has a range of co-factor roles, including being required for the activity of tyrosine and tryptophan hydroxylase, enzymes that are essential for dopamine and serotonin synthesis. They speculated that something present in the heroin pyrolysate, a product formed when heroin is heated to 250° C, inhaled by the patient, acted as a reversible inhibitor of tetrahydrobiopterin metabolism, providing a biochemical explanation for impairment of dopamine metabolism and Parkinsonism in this case. 

At least several weeks administration of virtually all antidepressant drugs, be they the classical tricyclic compounds or the newer selective serotonin reuptake inhibitors (SSRI), is required before patients see relief from their symptoms. A recently developed SSRI whose structure departs markedly from existing agents appears to differ from other agents, in that it appears to act in a much shorter time. The final step in the synthesis of this agent elzasonan (182) comprises aldol condensation of the benz-aldehyde (180) with the thiamorpholine (181). ... 

Ryckmans T, Balancon L, Genicot C, Berton O., Lamberty Y 91. Lallemand B, Pasau P, Pirlot N, Quere L, Talaga P. First dual NK(1) antagonists-serotonin reuptake inhibitors synthesis and... 

Asymmetric reduction of or y-functionalized alkyl aryl ketones provides a wide variety of chiral amino alcohols. Commercial -chloropropiophenone is reduced with borane-tetrahydrofuran adduct catalyzed by oxazaborolidine 45 to provide the chlorohydrin in over 99 % yield with 94 % ee. The resulting alcohol is a key intermediate for synthesis of the R form of fluoxetine (Prozac ), a serotonin-uptake inhibitor [53]. Using hydrogenation processes the functionalized amino ketones are converted directly into the respective products [8, 43e],... 

Duloxetine (LY-248686), (S)-(-i-)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propyl-amine, is expected to be not only a new potent antidepressant but also a NE (norepinephrine) reuptake inhibitor, a 5-HT (serotonin) reuptake inhibitor, and a new treatment drug for stress urinary incontinence [18]. In order to produce an enantiopure key intermediate for the synthesis of the (S)-amine, the Eli Lilly group proposed various strategies [19]. As a result, they selected the enantioseparation of racemic 3-(dimethylamino)-l-(2-thienyl)propan-l-ol with (S)-mandelic acid by diastereomeric salt formation as the most economic and suitable process for industrial-scale production with efficient supporting techniques such as the racemization of the antipode and recycling the recovered materials [20]. However, in the process of demethylation for the preparation of (S)-Duloxetine from (S)-3-(di-methylamino)-l-(2-fhienyl)propan-l-ol, there are some critical problems, such as low yield and considerable decomposition to give impurities. Thus, a direct synthesis of (S)-Duloxetine starting from (S)-3-(methylamino)-l-(2-thienyl)propan-l-ol is expected to be a new route for the production of (S)-Duloxetine. 

Ryckmans, T, Balan9on, L., Berton, O., Genicot, C., Lamberty, Y., Lallemand, B., Pasau, P, Pirlot, N., Quere, L., Talaga, P. First dual NKi antagonists-serotonin reuptake inhibitors synthesis and SAR of a new class of potential antidepressants. Bioorg. Med. Chem. Lett. 

Many reports have linked childhood hyperactivity to impaired central serotonin functions.89 In animals, the occurrence of a behavioral syndrome consisting of hyperactivity, stereotyped movements, and increase of temperature has been induced by L-tryptophan, as a serotonin precursor, by serotonin reuptake inhibitors, and by MAOIs.90 Most of these manifestations can be blocked specifically by pretreatment with an inhibitor of serotonin synthesis. In humans, the association of myoclonus, diarrhea, confusion, hypomania, agitation, hyperreflexia, shivering, incoordination, fever, and diaphoresis, when patients are treated with serotoninergic agents, could constitute a "serotonin syndrome." Such cases of serotonin syndrome were reported after treatments with L-tryptophan, MAOIs, serotonin reuptake inhibitors, and tricyclics, alone or in association. 

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