Serotonin, structure

FIGURE 4.5 The structures of some ammo acids that are not normally found in proteins but that perform other important biological functions. Epinephrine, histamine, and serotonin, although not amino acids, are derived from and closely related to amino acids. 

Trace amines are a family of endogenous monoamine compounds including (3-phenylethylamine (PEA), p-tyramine (TYR), tryptamine (TRP) and octopamine (OCT). The trace amines share close structural similarity with the well known classical monoamine neurotransmitters such as dopamine (DA), norepinephrine (NE) and serotonin (5-HT). As their name suggests, trace amines occur in comparably much lower abundance than monoamine neurotransmitters. For historical reasons, other endogenous amine compounds which might share some structural similarities with PEA, TYR, TRP or OCT are not referred to as trace amines. 

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. 

Nichols DE Studies ofthe relationship between molecular structure and hallucinogenic activity. Pharmacol Biochem Behav 24 335-340, 1986 Nichols DE Hallucinogens. Pharmacol Ther 101 131-191, 2004 Peroutka SJ Serotonin receptors, in Psychopharmacology The Third Generation of Progress. Edited by Meltzer HY. New York, Raven, 1987, pp 303-311 Perry PJ, Wilding OC, Juhl RP Anticholinergic psychosis. Am J Hosp Pharm 35 725— 728, 1978... 

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. 

Povlock, SL and Amara, SG (1997) The structure and function of norepinephrine, dopamine and serotonin transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 1-28. 

Schuldiner, S (1998) Vesicular neurotransmitter transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 215-240. Stanford, SC (1995) Central noradrenergic neurones and stress. Pharmac. Ther. 68 297-342. Stanford, SC (1999) SSRI-induced changes in catecholaminergic transmission. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austin, TX, pp. 147-170. 

Jacobs, BL and Azmitia, EC (1992) Structure and function of the brain serotonin system. Physiol. Rev. 72 165-229. 

Figure 20.5 The chemical structure of the selective serotonin reuptake inhibitors (SSRIs)...

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]. 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

Maricq, A. V., Peterson, A. S., Brake, A. J., Myers, R. M., and Julius, D. (1991). Primary structure and function expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254 432-437. 

Fig. 31. Example of neuroactive indole alkaloids from plants. Note the similitude of chemical structure of harmine, harmaline, and serotonin.

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