7-Substituted 5-hydroxytryptamine

The binding of 7-substituted-5-hydroxytryptamine derivatives to an LSD receptor site correlates with the frontier electron density (fj ) and charge of the ring nitrogen (position 1), modified by... 

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). 

Serotonin, A-methylserotonin, bufotenine, and 5-methoxy-A-methyltryptamine become readily available in a simple way by applying nucleophilic substitution reactions in 1-hydroxytryptamine chemistry (99H1157, 2001CPB87). 

In view of this neurotoxicity, we will review some data relevant to this process. First, we will review data showing that methamphetamine (METH), a prototypic psychomotor stimulant, which has been widely used for nonmedical purposes at doses often a good deal higher than therapeutie doses, is neurotoxic to dopamine (DA) and serotonin (5-hydroxytryptamine (5-HI)) systems. Second, we will examine the evidence that other substituted phenethylamines are also neurotoxic to certain transmitter systems. Last, we will examine the behavioral and pharmacological consequences of neurotoxicity that result from exposure to some of these amphetamine-related drugs. 

Ask, A.-L., and Ross, S.B. Inhibition of 5-hydroxytryptamine accumulation and deamination by substituted phenylalkylamines in hypothalamic synaptosomes from normal and reserpine-pretreated rats. Naunyn-Schmiedebergs Arch Pharmacol 336 591-596, 1987. 

Berger, U.V., Gu, X.F., Azmitia, E.C. The substituted amphetamines 3,4-methylenedioxymethamphet-amine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur. J. Pharmacol. 215 153, 1992. 

H, COOMe) from the appropriately substituted IV-hydroxytryptamine was also completed <00JCS(P1)3487>. 

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

In Section 1.3, the general effects of fluorine substitution on drug activity and selectivity have been treated. As seen frequently with other enzymatic reactions, introduction of fluorine can have dramatic effects on the properties of substrates and inhibitors of MAOs [26]. For example, preliminary studies indicated that fluorination of 5-hydroxytryptamine in the 6- or the 4,6-positions (3,4) causes this predominantly MAO A substrate to be metabolized significantly by platelet MAO B [27]. Although no direct evidence was obtained, this may be caused by increased lipophilicity introduced by fluorine substitution. 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

The psilocybin and psilocin molecular grouping bears a close resemblance to chemicals appearing in the brain. One of the psilocybian analogues is, in fact, one of the closest known compounds to the neurotransmitter serotonin, differing only with respect to the rare substitution just mentioned it is 4- rather than 5-hydroxytryptamine. Psilocin, interestingly, is the nearest relative to bufotenine, once thought a psychoactive compound,... 

MDL 73147EF) is a substituted quinolizinylindole, a selective (5-HT3) 5-hydroxytryptamine receptor antagonist. It shows ANTIEMETIC activity against chemotherapy-induced emesis, and also has antimigraine activity, dolasetron mesylate dolasetron. 

GR 87442 N) is a substituted pyridoindolone, a (5-HT3-subtype) 5-hydroxytryptamine receptor antagonist. It has potential as an antinauseant or ANTIEMETIC, lurosetron mesylate lurosetron. 

ML 10302 (RS 70678) is a substituted benzamide and analogue of metoclopramide, and is a (5-HT4-subtype) -HYDROXYTRYPTAMINE RECEPTOR AGONIST. 

Eudistomidin A (11) and eudistomins H (7), I (8) and P (9) have been made (127, 128) by the Bischler-Napieralski (BN) reaction, a method used extensively by the Hino group. Appropriately substituted tryptamine was condensed with BOC-prolinoyl chloride, then treated under BN conditions (POCl3 or polyphosphoric ester (PPE)) to produce a 5,7-disubstituted eudistomin skeleton (163). Eudistomin I thus results when starting from tryptamine (Scheme 9, R = R = H), eudistomin H from 5-bromotryptamine (Scheme 9, R = Br, R = H), eudistomidin A from 5-bromo-7-hydroxytryptamine (Scheme 9, R = Br, R = tosylate) eudistomin P is obtained from the use of 6-bromo-5-methoxytryptamine. 

The formation of (49) (Table 6) may be considered as new evidence for the presence of a spiro-indolenine intermediate in the Pictet-Spengler reaction of N -hydroxytryptamine <88CC463>. Thus A-substituted N -hydroxytryptamines with cysteinals afforded only (49 R = Me, CHjOMe). In similar reactions with N -hydroxytryptamines, (49 R = H) was formed along with ) -carboline derivatives. 

Lessin, A.W. Long, R.F. Parkes, M.W. 1967. The central stimulant properties of some substituted indolealkylamines and 6-carbolines and their activities as inhibitors of monoamine oxidase and the uptake of 5-hydroxytryptamine. British Journal of Pharmacology and Chemotherapy Vol. 29 70-79. 

---