Psychedelic Drugs Rediscovered-In Silico Study of Potential Fetal Exposure to Analogues of Psychedelic Drugs During Pregnancy.

Most of 250 compounds from three chemical families (ergolines, tryptamines, and phenylethylamines), including ketamine and serotonergic psychedelics, are likely to cross the human placenta easily, primarily by passive diffusion. A multivariate model based on drug-likeness, Caco-2 membrane permeability, protein binding, volume of distribution, and heteroatom count predicted this passage. Atomic contributions from Morgan fingerprinting suggest that carbonyl, hydroxyl, nitro-, and phosphoryloxy groups promote placental transport, while rigid polycyclic structures, bulky alkyl/aryl groups, and halogens restrict it. All compounds are expected to be synthetically accessible, raising concerns about illegal drug production and the need for further in silico pharmacological study.

Study at a glance

Abstract

A total of 250 known and novel compounds-ketamine and serotonergic psychedelics or their analogues-designed to target depression, addictions and/or other mental or neurological disorders and developed as "recreational" (illegal) drugs from three chemical families, ergolines, tryptamines and phenylethylamines, were investigated in the context of their ability to cross the human placenta. Using a novel multivariate model involving compounds' drug-likeness (according to Lipinski's Ro5), caco-2 membrane permeability, fraction unbound to plasma proteins, steady-state volume of distribution and the total count of heteroatoms (non-carbon atoms with hydrogens included), it was established that the majority of studied compounds are likely to cross the placenta easily, most probably by the passive diffusion mechanism. Atomic contributions of structural elements of studied compounds were investigated using the Morgan fingerprinting algorithm and it was postulated that the fragments promoting transport of compounds across the placenta are carbonyl, hydroxyl, nitro- and phosphoryloxy groups-rigid polycyclic structures, bulky alkyl/aryl groups and halogen atoms restrict the trans-placental passage. All studied compounds are expected to be relatively easily obtained by synthetic routes, which makes them an interesting target for manufacturers of illegal drugs and warrants the need to pursue pharmacological studies of these compounds in silico.