Of serotonin

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Desipramine [50-47-5] (35) and nortriptyline [72-69-5] (36) are demethylated derivatives and principal metaboHtes of (32) and (33), respectively. Both compounds possess less sedative and stronger psychomotor effects than the tertiary amine counterparts, probably because tricycHcs containing secondary amine groups generally show greater selectivity for inhibiting the reuptake of norepinephrine compared with the reuptake of serotonin. Protriptyline [438-60-8] (37), a stmctural isomer of nortriptyline, is another important secondary amine that displays a similar clinical profile. 

Other studies indicate that sucrose does not cause hyperactivity. Carbohydrate ingestion increases levels of serotonin (5-hydroxytryptamine), a brain neurotransmitter that promotes relaxation and sleep. Dietary sucrose should theoretically have a calming effect and reduce activity, manifestations which have been observed in case studies (63). To date, clinical investigations have failed to show a significant connection between sucrose consumption and aggressive or dismptive behavior (66). 

The procedure was largely ignored until the 1950s when interest in melanin-related substances and recognition of serotonin as a 5-hydroxy derivative stimulated exploration of the scope of the reaction. Nowadays, the Nenitzescu reaction is one of the most efficient processes for the preparation of 5-hydroxyindoles. 

This review is an attempt to collect under one heading and to present in a systematic manner the large body of work which deals with the chemistry of the carboline ring systems. Some three hundred papers in this field have been published during the last decade, more than twice as many as appeared during the preceding fifty years. The renewed interest in the chemistry of the carbolines is due in no small measure to the discovery of serotonin and to the recent developments in the chemistry and pharmacology of the Rauwolfia and related alkaloids. 

In contrast, substrates having other struetural types of side ehain at the 3 position dimerize under aeidie eonditions, and never produee the 5-substituted produets. These faets seem to support the 1-Hydroxyindole Hypotheses, whieh elaim the formation of serotonin from 1-hydroxytryptophan and/or -tryptamine in the aeidie eompartment within eukaryotie eells. 

The involvement of serotonin (5-hydroxytryptamine) in disease states has been recognized for several decades. Research on antagonists awaited the recent development of methodology involving serotonin receptors. A thiazolopyrimidone serves as the nucleus for a pair of serotonin antagonists. The key intermediate 118 is in fact simply the lactonized form of 2-hydroxyethyl acetoace-tate. Condensation of this P-keto ester can be visualized to involve initial attack on the reactive... 

Richardson, B. P., Engel, G., Donatsch, P., and Stadler, P. A. (1985). Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316 126-131. 

Sibutramine (Table 1) has been in the market for several years and inhibits the reuptake of serotonin, noradrenaline and, to a lesser extent, dopamine. It acts... 

Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21 106S—115S... 

Dopa decarboxylase is an enzyme catalyzing the synthesis of dopamine from l-DOPA or of serotonin (= 5-hydroxytryptamine) from L-tryptophan. Inhibitors of this enzyme, which do not pass through the... 

The most widely used emetic is syrup of ipecac, containing the alkaloids, emetine and cq haeline. Emetine induces vomiting by activation of sensory neurons in the vagus and sympathetic nerves to the stomach and centrally in the medulla, possibly at the CTZ. The release of serotonin and SP may be involved as 5-HT3 and NKi receptor antagonists prevent emesis induced... 

Cytotoxics also cause cellular damage and the release of serotonin and other mediators from enterochromaffin cells. There is conflicting evidence regarding whether 5-HT3 receptors in the medulla are activated also during chemotherapy and contribute to production of emesis. Currently, the weight of evidence favours peripheral 5-HT3 receptors, with minor involvement of central receptors. 

Methylenedioxymethamphetamine (MDMA ecstasy) is a synthetic analog of amphetamine that produces hallucinations, an elevation in mood, and a feeling of emotional closeness . This latter property has led to Ecstasy being referred to as the hug drag . The unique properties of Ecstasy as compared to the parent compound amphetamine are believed to be due to the more selective effects of Ecstasy in promoting transporter-mediated release of serotonin. The use of Ecstasy has become a part of the culture associated with rave style dance parties. 

Antidepressive agents which increase synaptic availability of serotonin and noradrenaline have been empirically found to be efficacious against chronic pain, particularly that of neuropathic origin. 

Serotonin or 5-hydroxytryptamine is an important biogenic amine, which is synthesized via 5-hydroxy-tryptophan from the amino acid tryptophan. The highest concentration of serotonin occurs in the wall of the intestine. About 90% of the total amount is present in enterochromaffrn cells, which are derived from the neural crest, similarly to those of the adrenal medulla. 

TK NKxr displays a broad distribution in both peripheral tissues and in the central nervous system (CNS). In both CNS and enteric neurons, NKxr stimulation increase their excitability, whereas in trigeminal ganglion neurons SP has no intrinsic electrophysio-logical effects but is capable to enhance the amplitude of the inward current induced by the stimulation of serotonin 5-HT3 recqrtors. This enhancement dqjends on the activation of PKC via the stimulation of NKX recqrtors. This is an interesting case of receptor cross talk. Other functions of NKxr have been also highlighted. 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

Rodd-Henricks ZA, McKinzie DL, Melendez Rl, et al Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats. Psychopharmacology (Berl) 165 252—259, 2003... 

Boadle-Biber, MC (1993) Regulation of serotonin S5mthesis. Prog. Biophys. Molec. Biol. 60 1-15. Curzon, G, Gibson, EL and Oluyomi, AO (1997) Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability. Trends Pharmacol. Sci. 18 21-25. Gaddum, JH and Picarelli, ZP (1957) Two kinds of tr5 ptamine receptor. Brit. J. Pharmacol. 12 323-328. (Reproduced in Brit. J. Pharmacol. 120 (Suppl) 134-139.)... 

Povlock, SL and Amara, SG (1997) The structure and function of norepinephrine, dopamine and serotonin transporters. In Neurotransmitter Transporters. Humana Press, New York, pp 1-28. Ramamoorthy, S and Blakely, RD (1999) Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285 763-766. 

Arylpiperazines have immensely important effects on various and diverse biological targets, in particular on CNS receptors. In the case of serotonin (5-HT) receptors, compounds containing this arylpiperazine moiety represent the largest systematically studied class of 5-HTia receptor ligands [63]. Structural alterations within long-chain arylpiperazines (LCAPs) occur mainly at the two opposite ends of a molecule and have been described by many authors [64-71]. 

The asymmetric reductive ring opening of oxabenzonorbomene 53 was applied as a key step in the total synthesis of serotonin re-uptake inhibitor sertraline [77, 80]. 

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