In Silico Study of Morphine-Like Effects of Ethanol Intake: Docking of Acetaldehyde Conjugates with Monoamines to the Mu-Opioid Receptor

Addiction to alcohol is one of the main problems in society. Currently, several biochemical mechanisms underlying the development of alcoholism have been discovered. Ethanol (C2H5OH) was shown to be able to interact directly with several receptors on neural cells (nicotinic acetylcholine receptors [1], G proteingated inwardly rectifying K+ channels [2], glycine receptors [3], gamma-aminobutyric acid receptors [4], N-methyl-D-aspartate receptors [5]). Consequences of such binding are thought to cause mental effects of a low dose alcohol intake (such as excitation and anxiolytic effect). Of course, ethanol should also be able to interact with many other receptors and even enzymes [6,7] contributing to the mental effects development. Ethanol is metabolized in cells by alcohol dehydrogenases. The product of ethanol oxidation by that family of enzymes (acetaldehyde CH3CHO) is more reactive than ethanol itself. It is known that acetaldehyde can form conjugates with biogenic amines (with dopamine, serotonin, tryptamine, and tryptophan) both spontaneously and with the help of enzymes [8,9]. Such conjugation results in the formation of an additional ring. Conjugates of abovementioned biogenic amines and acetaldehyde demonstrate some structural similarities with morphine [10]. For this reason, they were thought to bind muopioid receptors and cause morphine-like effects after high dose alcohol intake (stimulation, reinforcement, and then sedation, loss of consciousness, and amnesia) [11]. The most studied conjugate of acetaldehyde and biogenic amine is known under the name salsolinol [8]. That compound (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) can be produced from dopamine and acetaldehyde. Interestingly, salsolinol is naturally produced in neural tissue and, probably, plays some role in neurotransmission [8]. During the high dose alcohol intake, its concentration grows to a level that is much higher than the background one [11]. Biodegradation of salsolinol includes at least two steps. First, salsolinol is methylated by N-methyltransferase (the product is 1,2-dimethyl-6,7-dihydroxy1,3,4-trihydroisoquinoline) [12]. Then N-methyl-salsolinol is oxidized by amine oxidase and forms 1,2-dimethyl-6,7dihydroxyisoquinolinium ion [12].