LSD deconstruction reveals promising new drug candidates

In a study published in Proceedings of the National Academy of Sciences, the researchers whittled away at LSD's core multi-ring structure and synthesized new, simplified versions of it to probe its functionality. The researchers successfully developed several compounds with reduced hallucinogenic and cardiotoxic effects while also identifying one compound that produced antipsychotic-like effects.

LSD is among the many psychedelic drugs that researchers are investigating due to its ability to spur growth of neurons and strengthen connections between them. A host of neuropsychiatric and neurodegenerative diseases are characterized by these connections withering.

Finding function in the framework

The research focused on LSD's ergoline core, which is a structure of four fused ring-like shapes that act as its base molecular scaffold. This structure interacts with a suite of serotonin receptors in the brain, including serotonin receptors 5-HT2A, 5-HT2B and 5-HT2C, to produce LSD's various positive and negative effects.

In total, the research team synthesized nine modified versions of LSD's ergoline core, two of which showcased these improved safety profiles, with reduced hallucinogenic and cardiotoxic effects.

A paradoxical-like quality

"It's interesting that you could take LSD's structure, chop off a part of it and you're left with a molecule that is fundamentally antipsychotic," said Olson, noting that compounds that activate 5-HT2C receptors are being explored as treatment options for epilepsy and substance use disorders in addition to schizophrenia. "This is a great starting point for those conditions."

Source:

University of California - Davis

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