Effects of Deuterium Substitution on the Catabolism of β‐Phenylethylamine: An In Vivo Study

Abstract

beta-Phenylethylamine (PE) hydrochloride injected intraperitoneally into rats was distributed evenly throughout the various regions of rat brain. Similarly, when a mixture of PE and alpha, alpha, beta, beta-deuterated PE [( 2H4]PE) was injected, no regional differences were observed in the ratios of the amounts of [2H4]PE and PE present; however, significantly more [2H4]PE than PE was present, although a 1:1 mixture had been administered. Further experiments in which the amounts of [2H4]PE and PE in whole rat brain, liver, and plasma were quantified confirmed this finding. The maximum [2H4]PE-to-PE ratios observed were 67 in whole brain 1 h after injection and 8 in liver and in plasma 45 min after injection. The whole brain [2H4]PE-to-PE ratios were decreased by pargyline pretreatment. Subsequent experiments showed that more alpha, alpha-[2H2]PE than PE was present in whole brain, liver, and plasma of rats injected with an equimolar mixture of alpha, alpha-[2H2]PE and PE. In contrast, beta, beta-[2H2]PE was not enriched in comparison to PE under the same experimental conditions. We concluded that the basis for the enrichment of [2H4]PE and alpha, alpha-[2H2]PE compared to PE was due to protection of the deuterated analogs from the actions of monoamine oxidase and perhaps aldehyde dehydrogenase; this protection led to pronounced deuterium substitution effects in vivo especially in the brain.

The origin of palmitic acid in brain of the developing rat

“…A very low uptake of deuterium labeled fatty acid into brain and a large deposition into liver and other organs were observed (9). Waelsch and associates {9,23,24) concluded that "the brain synthesizes the fatty acids it needs, wholly or in large part, and does not depend on an external source of supply:' Perdeuterated and deuterated substances are known to have access to the brain (25)(26)(27)(28)(29) and have been used to study the half lives of rapidly metabolized drugs, because they are not degraded as quickly as the unlabeled forms (26)(27)(28)(29). During the seven-day period of our study, a large net increase in ~ fatty acids and palmitic acid occurred in the liver and to a greater extent in brain.…”

2‐Phenylethylamine: A Modulator of Catecholamine Transmission in the Mammalian Central Nervous System?

“…The recent development of prodrugs of PE may allow more subtle investigations of the effects of PE on behavior; because N-(2-cyanoethyl)-2-phenylethylamine and N,N-dipropargyl-2-phenylethylamine are metabolized slowly to release PE, this results in long-lasting increases in the concentration of PE in the CNS but avoids the initial peak concentrations Rao et al, 1987). Use of deuterium-substituted PE may also be possible: Because of isotope effects, it is deaminated slowly ( Yu et al, 1981;Dyck et al, 1986).…”

Deuterated drugs: where are we now?

“…Examining these rejections shows the development of similar arguments for rejection that typically are based around firstly discussing the motivation to prepare deuterated versions of drugs to obtain versions with better pharmaceutical properties, typically supported by reference to Dyck et al [71] ‘Thus deuterium substitution seems to be a useful strategy to enhance the pharmacological effects of a compound without significantly altering its basic chemical structure’ although other references [72, [73] from this group might also suffice, and Dyck is not cited in all such rejections. Support for the generality of this approach is then derived from referenced such as Ando et al , [43] Foster et al [28].…”