Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson’s disease, and addiction. Synthetic phenethylamines can have psychoactive and hallucinogenic effects due to their high affinity with the 5-HT2A receptor. Evidence indicates phenethylamines can directly alter the microtubule cytoskeleton being structurally similar to the microtubule destabilizing agent colchicine, however little work has been done on this interaction. As microtubules provide neuron structure, intracellular transport, and influence synaptic plasticity the interaction of phenethylamines with microtubules is important for understanding the potential harms, or potential pharmaceutical use of phenethylamines. We investigated 110 phenethylamines and their interaction with microtubules. Here we performed molecular docking of these compounds at the colchicine binding site and ranked them via binding energy. The top 10% of phenethylamines were further screened based on pharmacokinetic and physicochemical properties derived from SwissADME and LightBBB. Based on these properties 25B-NBF, 25C-NBF, and DMBMPP were tested in in-vitro microtubule polymerization assays showing that they alter microtubule polymerization dynamics in a dose dependent manner. As these compounds can rapidly cross the blood brain barrier and directly affect cytoskeletal dynamics, they have the potential to modulate cytoskeletal based neural plasticity. Further investigations into these mechanisms are warranted.

Microtubules are important for the formation of the cytoskeleton and mitotic spindles, and they aid in cell movement and intracellular transport. Therefore, they are important for cell survival and cell function. Microtubules are composed of the alpha‐beta tubulin heterodimer protein. During polymerization tubulin proteins experience phases of dynamic instability, which is characterized by microtubule growth and shrinkage at varying rates. Microtubule formation can be inhibited by compounds such as colchicine, a known microtubule destabilizing agent, that binds to tubulin to block polymerization. In this study we investigated one hundred eleven compounds that had a similar structure to colchicine. We used AutoDock Vina to dock each compound including colchicine to tubulin in the same binding site as colchicine. The binding energy of colchicine was ‐10.9 kcal/mol, and the binding energies of the top 10% binding affinity compounds were between ‐9 kcal/mol and ‐7.9 kcal/mol. The pharmacokinetic properties of these drugs, computational binding affinity and similarity to colchicine show promise as novel inhibitors of microtubule polymerization, which will be further explored through laboratory experiments.