Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships

Abstract

A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines, and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting. There is a discussion of receptor binding, electrical effects, cell signaling and other modes of action. Mescaline is a nonselective, seretonin receptor agonist. 5-HTP receptors are involved in the stimulus properties. Research addresses the aspect of stereochemical requirements. Receptor binding may involve the proposed quinone metabolite and/or the amino sidechain via protonation. Electroencephalographic studies were performed on the effects of mescaline on men. Spikes are elicited by stimulation of a cortical area. The potentials likely originate in nonsynaptic dendritic membranes. Receptor-mediated signaling pathways were examined which affect mescaline behavior. The hallucinogen belongs to the class of 2AR agonists which regulate pathways in cortical neurons. The research identifies neural and signaling mechanisms responsible for the biological effects. Recently, another hallucinogen, psilocybin, has been included within the unifying mechanistic framework. This mushroom constituent is hydrolyzed to the phenol psilocin, also active, which is subsequently oxidized to an ET o-quinone or iminoquinone.

Scheme 1

Biosynthesis of mescaline. Steps include oxidation of (2) to (3), decarboxylation to (4), oxidation to (5) and methylation to (1).

Scheme 2

Synthetic routes to mescaline. Various routes have been reported for laboratory synthesis of mescaline. Key starting materials incorporate acetal, nitro alkene and chromium complex.

Figure 1

Catechol and o-quinone metabolites of mescaline. The catechol-type metabolite (6) is part of a class that readily undergoes redox cycling with generation of an o-quinone product (7). The process is an oxidative transformation. In addition, the catechol group readily complexes with heavy metals. Generally, such complexes are known to undergo electron transfer reactions which, in the brain, may be involved in some of the physiological effects elicited by mescaline.

Figure 2

In vivo metabolism products of mescaline. These include demethylation and side chain modification.

Figure 3

In vitro metabolic intermediates of mescaline. The process entails monodemethylation to phenolic diethers.

Figure 4

Sidechain homolog of mescaline. The data show that homologation of the sidechain to the isopropyl structure enhances the potency. This side chain is also present in Figure 5.

Figure 5

2,5-Dimethoxyphenyl analog of mescaline. This analog on demethylation would yield a hydroquinone which could undergo redox cycling with its p-quinone partner.

Figure 6

Metabolism of psilocybin to o- and imino-quinones. The process entails dephosphorylation to the phenol followed by oxidation to quinone-type products.

Figure 7

Hallucinogens. These psychic drugs are used in comparison studies involving physiological activity.