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It has been established that the oxidative deamination of tyramine by monoamine xodase is inhibited by (+/-)-4-methoxy-beta-hydroxyphenethylamine and its N-methylated derivatives. This particular series of compounds does not inhibit the action of monoamine oxidase when tryptamine is used as the substrate. In contrast, 4-methoxyphenethylamine and its N-methylated homologs inhibit the monoamine oxidase-catalyzed deamination of both tyramine and tryptamine.

The Dona Ana cactus, Coryphantha macromeris (Engelm.) Br. and R. and its runyonii (Br. and R.) L. Benson variety are being promoted as natural and legal psychedelic agents with about one-fifth potency of peyote [Lophophora williamsii (Lem.) Coult.]. Like peyote, Dona Ana produces and accumulates various methylated catecholamine derivatives. Of these phenethylamines, normacromerine (N-methyl-3,4-dimethoxy-beta-hydroxyphenethylamine) is by far the most abundant and has been shown to affect animal behavior in such a way as to suggest psychoactivity. It has been demonstrated that the catecholamines epinephrine and norepinephrine occur naturally in C. macromeris var. runyonii and serve as biosynthetic intermediates in normacromerine biosynthesis. Catecholamine precursors and derivatives have also been shown to be part of the metabolic pathway leading to the formation of normacromerine in Dona Ana. Normacromerine appears to be the end product of catecholamine metabolism since recent studies have revealed that very little of this compound is metabolized once it has been formed by the cactus. Completed research of this type has allowed the comparison of catecholamine metabolism leading to the formation of a mind-altering drug in a cactus plant and the metabolism of catecholamines in humans. These data together with evidence from future research will allow biochemical analogies which may suggest etiologies for certain types of mental illness.

The synthesis and selected pharmacological testing of (+/-)-4-methoxy-beta-hydroxyphenethylamine [1-(4-methoxyphenyl)-2-aminoethanol] and its N-methylated derivatives are presented. Members of this series were found to exert partial prevention of reserpine-induced hypothermia in mice and to inhibit monoamine oxidase in Warburg studies. Activity was essentially dose dependent. The secondary amine was the most active member of the series. The tertiary amine was least active, and the primary amine exhibited intermediate activity.

The biosynthetic conversion of epinephrine to normacromerine in Coryphantha macromeris (Engelm.) Br. and R. var. runyonii (Br. and R.) L. Benson (Cactacae) has been studied. Metanephrine, which has been isolated from this cactus and is a normal metabolite of epinephrine in mammalian systems, appeared to be the likely intermediate between epinephrine and normacromerine. Normacromerine turnover studies suggested a 16-day interval between metanephrine administration and harvest of the cacti. During this incubation period, the cacti specifically converted 4.77% of the administered DL-7-3H-metanephrine to normacromerine. Based on biochemical precedents, the postulated metabolic fate of normacromerine in the cactus was an enzymatic N-methylation to give macromerine. However, radiolabeled normacromerine was a very ineffecient precursor to macromerine.

The cactus alkaloid 3,4-dimethoxyphenethylamine and its naturally occurring N-methylated homologs inhibited the deamination of tyramine and tryptamine by rat brain monoamine oxidase. In contrast, the beta-hydroxylated derivatives of this series failed to inhibit the action of monoamine oxidase on both tyramine and tryptamine.