Harmaline derivatives

Spath and Lederer have published a simplified synthesis of harmaline consisting in treating the acetyl derivative of 6-methoxytryptamine (XXIX) with phosphorus pentoxide in boiling xylene, the harmaline thus produced being converted into harmine by catalytic dehydrogenation at 200°. 

Non-oxidative conversion of a tetrahydro-)8-carboline into a 3,4-dihydro derivative has also been described. Dehydration of 1-hydroxymethyl-1,2,3,4-tetrahydro-j8-carboline (146) yielded 1-methyl-3,4-dihydro-j8-carboline (135). Harmaline and l-methyl-3,4-dihydro-j8-carboline-3-carboxylic acid were obtained in an analogous manner. ... 

Nitration of quinindoline gave the expected 9-nitro derivative (261). A single mononitro compound was formed from the 3,4-dihydro-jS-carboline, harmaline this was 6-nitroharmaline, since on oxidation it yielded 3-nitro-4-methoxybenzoic acid. 

Quaternization with alkyl halides of 3,4-dihydro-jS-carboline and its derivatives takes place at the pyr-N. Quaternary 3,4-dihydro-j8-carbolinium salts (309) derived from harmaline, 3,4-dihydro-j8-carboline, 6-methoxy-3,4-dihydro-j8-carboline, and 1 -methyl-3,4-dihydro-j8-carboline have been described. Further... 

The Eschweiler reaction (formaldehyde and formic acid) has been used for the pyr-A-methylation of l-methyl-l,2,3,4-tetrahydro-j8-carboline, as has formaldehyde and hydrogen in the presence of Raney nickel. Tetrahydroharmine has been reported to react with benzaldehyde to yield a condensation product, C33H36N403, which is presumably a pyr-iV-substituted derivative (318). It is not known whether a similar condensation product of benzaldehyde with harm-aline is a C- or V-substituted derivative of harmaline. Conden-... 

It has been postulated that harmaline itself may under certain conditions consist of an equilibrium mixture of the isomeric structures 122 and 441, with the former strongly predominating . Both forms are regarded as existing in equilibrium with the harmalinium cation (440), from which the former may be derived by deprotonation at the... 

These authors formulated the major steps in the biogenesis of the harmala bases as a condensation of a tryptamine derivative (460) with acetaldehyde to yield a l,2,3,4-tetrahydro-)3-carboline (461), which on oxidation in two stages would give harmaline (462 R = OCH3) and then harmine (463 R = OCH3). 

In summary, based on the results of relatively limited studies, the dihydro beta-carboline, harmaline (80), is more active than either its fully unsaturated derivative harmine (79) or its reduced derivative tetrahydroharmine (81). The positional isomer of harmine, 6-methoxyharmalan (85), is slightly more potent than harmaline. Reduction to the tetrahydro derivative 86 reduces potency. Although thorough dose-effect studies have not yet been performed, none of the beta-carboline derivatives has been found to be significantly more potent than DMT (37). 

Back to the individual chemical stories. This commentary will cover the scatter of beta-carbolines that might play some major role in the human nervous system, other than the harmine trilogy. Harmine, harmaline and tetrahydroharmine all have the oxygen at the 7-position, and mostly have their origins in the botanical world. The 6-position oxygen can come directly from serotonin or hydroxy-tryptophan, and are found both in plants and animals. Similarly, the hydrogen derivatives (unsubstituted) derive from tryptamine and tryptophan, again from both plants and animals. 

I want to mention that this alkaloid is of special interest because of its close resemblance to substances derived from the pineal gland of mammals. In particular, 10-methoxy-harmaline, which may be obtained in vitro from the incubation of serotonin in pineal tissue, resembles harmaline in its subjective effects and is of greater activity than the latter. This suggests that harmaline (differing from 10-methoxy-harmaline only in the position of the methoxy group) may derive its activity from the mimicry of a metabolite normally involved in the control of states of consciousness. 

The structure of harman (II R = H) has been discussed already in connection with that of harmaline. Many additional syntheses of it and of its tetrahydro derivative have been recorded (39-44). Owing to the extremely active 2-position in the indole nucleus, cyclizations which yield quinolines from /3-phenethylamines proceed with greater ease from tryptamines, often yielding the tetrahydro bases under so-called physiological conditions (43, 44). A novel synthesis of harman depends upon... 

The ionization constants of the first excited states of p-carboline and three of its derivatives - harmane. harmine, and 2-methylharmine - have been re-ported, and the fluorescence and phosphorescence spectra of harmine, harmaline, and 3-dehydroreserpines have been determined in neutral, acidic, and basic solution at 298 and 77 K. The photo-oxidation of 3-dehydroreserpines has also been examined in this work. The luminescence spectra of a series of indole alkaloids have also been reported by the same workers. The effect of pH on the absorption and fluorescence spectra of sanquinonine, a benzophenanthridine alkaloid, have been studied in detail. 

In order to explain the Na stimulation of ATP synthesis driven by a diffusion potential the presence of a Na /H antiporter was proposed [175]. In this artificial system the acidification of the cytoplasm, which occurs in response to electrogenic potassium efflux, could be prevented by the antiporter. Subsequently, Na /H antiporter activity has been demonstrated in both Methanobacterium thermoautotrophicum [176] and in Methanosarcina harden [108]. An important result of these studies was that the Na /H antiporter could be inhibited by amiloride and harmaline, which have been described as inhibitors of eucaryotic Na" /H" antiporters [177]. Using these inhibitors it has been shown that an active antiporter is essential for methanogenesis from H2/CO2 [176,178]. The antiporter also accepts Li instead of Na, since Li stimulates CH4 formation from H2/CO2 in the absence of Na [176]. In subsequent studies the use of amiloride and the more potent derivative ethyl-isopropylamiloride permitted the discrimination of primary and secondary Na potentials generated in partial reactions of the CO2 reduction pathway. 

Fig. 9A Harmalae semen. The carbolin derivatives harmalol (Tl), harmaline (T2) and harmine (T4) are found as bright blue fluorescent zones in solvent A in the R, range 0.1-0.75. The Harmalae semen sample 1 shows as major alkaloids harmalol and harmaline in the low Rf range 0.05-0.25 and harmine in the upper Rf range 0.75.

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