Hydroxytryptamine structur

Meanwhile Rapport and his colleagues had been investigating the vasoconstrictor substance in serum which they named serotonin, and isolated in 1948 (693, 694). The isolated material was shown (692) to be a complex of creatinine with what was thought to be 5-hydroxytryptamine (structure diagram 23) and identification of the latter was confirmed by synthesis (19, 341, 363, 821). It then became clear that enteramine and serotonin were identical (e.g., 238, 239), and an enormous amount of work on the physiology and pharmacology of 5-hydroxytryptamine has subsequently appeared (reviews 235a, 237, 660, 958). 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

Leptosins D-F (258a-c, Scheme 39) [94JCS(P1)1859] were isolated by Takahashi and co-workers from the culture of a strain of Leptosphaeria sp. as cytotoxic substances against the P388 lymphocytic leukemia cell line comparable to that of mitomycin C. Utilizing the nucleophilic substitution reaction of 1-hydroxytryptamines, a simple methodology for the synthesis of core structures of leptosins has been developed (2000H1255). 

Tryptamine itself is found in all major centers of the brain. Its physiologic role in central nervous system (CNS) function, however, remains unclear. 5-Hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter in the CNS. The structural similarity of the tryptamine-related hallucinogens with 5-HT presumably forms the neurochemical basis for their action within the CNS. 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

FIGURE 13-1 Chemical structure of 5-hydroxytryptamine (5-HT serotonin) and related indolealkylamines. The indole ring structure consists of the benzene ring and the attached five-member ring containing nitrogen. 

Peters JA, Garland JE, Cooper MA, Livesey MR, Deeb TZ, Hales TG, Lambert JJ (2006) Novel structural determinants of single-channel conductance in nicotinic acetylcholine and 5-hydroxytryptamine type-3 receptors. Biochem Soc Trans 34(5) 882-886 Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391 173-177... 

Pridefine (80) is a somewhat structurally related antidepressant. It is a centrally active neurotransmitter blocking agent. It blocks norepinephrine in the hypothalamus but does not affect dopamine or 5-hydroxytryptamine. Its synthesis be-(jins by lithium amide-promoted condensation of diethyl succinate and benzophenone followed by saponification to 78. Heating in the presence of ethylamine gives N-ethylsuccinimide 79. Lithium aluminum hydride reduction completes the synthesis of pridefine (80)... 

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter. 

Dihydrocorynantheine (86), in turn, along with other structurally related alkaloids, has been found to decrease specific [3H]-5-hydroxytryptamine (5-HT) binding to membrane preparations from rat... 

Figure 7.3. Structural formulae of the noradrenaline (norepinephrine)/dopamine reuptake inhibitor amfebutamone (bupropion) and some nonselective noradrenaline and serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (venlafaxine, and...

Fluorescence histochemistry using antibodies to identify the compounds under investigation. Compounds with a 2,3-benzpyrrole structure. The indoleamines, e.g. 5-hydroxytryptamine, are compounds containing the indole structure. 

Povlock, S. L. and Amara, S. G. The structure and function of noradrenaline, dopamine and 5-hydroxytryptamine transporters. In Neurotransmitter Transporters. Totowa, NJ Humana Press, 1999, pp. 1-28. 

Lopez-Rodriguez ML, Vicente B, Deupi X, et al. Design, synthesis and pharmacological evaluation of 5-hydroxytryptamine(la) receptor ligands to explore the three-dimensional structure of the receptor. Mol Pharmacol 2002 62 15-21. 

The serotonergic system is involved in a large number of physiological functions, resulting from its widespread innervation of the brain. The axons of serotonergic neurons of the midbrain raphe nuclei reach almost every brain structure. Action potentials traveling along these axons release 5-hydroxytryptamine... 

Since they are tryptamine derivatives, the indolic hallucinogens are structurally related to the neurohumoral factor serotonin (5-hydroxytryptamine). Serotonin is widely distributed in warmblooded animals. It accumulates in the brain, where it plays a role in the biochemistry of nervous regulations. Consequently, it seems that certain tryptamine structures which occur so frequently in hallucinogens, as well as in the neurohormone serotonin, may be biochemically important in the metabolism of psychic functions. . . ... 

Indolealkylamines. GC-MS methods applied in studies of the biochemical pharmacology of indoleamines parallel work on the catecholamines. SIM assays for serotonin (5-hydroxytryptamine), 5-methoxytryptamine, JV-acetylserotonin and melatonin (5-methoxy-N-acetyltryptamine) in rat pineal and brain tissue have been described [453,469]. Pentafluoro-propionyl derivatives and structural homologue standardisation were employed with detection limits in the subpicomole range. Estimation of central indoleamine turnover in man currently depends upon metabolite determination in CSF. Ion monitoring determination of indole-3-acetic acid [454] a metabolite of tryptamine, and isotope dilution assays for 5-hydroxyindoleacetic acid (5-HIAA) [455,458] have been reported. Serotonin is converted by central monoamine oxidase to 5-HIAA and the measurement of this metabolite, formerly by fluorimetry, is of interest in patients with CNS disorders [470]. GC-MS has also contributed to the identification of N,N-dimethyltryptamine in vitro [471] and isotope dilution technique has been applied to the measurement of this metabolite in control subjects and in psychiatric patients [472]. 

BMY 13805-1 MJ 13805) is one of the azaspirone group structurally related to buspirone and with similar properties. It is a 5-hydroxytryptamine receptor agonist, a partial agonist at the 5HTi receptor subtype. It is a novel ANXIOLYTIC under investigation for treatment of anxiety and depression. 

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