Rationale

Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT 2A ) receptors.

Objectives

This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects.

Methods

Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter® assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors.

Results

Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT 2A , serotonin 1A (5-HT 1A ), and 5-HT 2A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT 2A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT 1A agonists. Most tryptamines recruited β-arrestin through 5-HT 2A activation.

Conclusions