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Author
Giraldo Mejia, Manuela
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Abstract
Over the last decade, the emergence of new drugs of abuse that are designed to circumvent legislation by slight chemical structural modifications of already classified drugs represents an ever increasing problem. It’s remarkable that they are sold openly in “head shops”, web-based shops and elsewhere and thereby reach new drug users that are attracted by their so-called “legal” status, being a major risk to public health. Among these substances, new synthetic tryptamines are one of the most prevalent classes of designer drugs that became popular, due to the similar hallucinogenic properties to already controlled psychedelics such as LSD. Nevertheless, there is minimal basic research on these drugs and most of these chemicals have not been safety profiled on humans or animals and there is minimal information about their mechanism of action.
Besides the lack of information, these compounds are known to interact with various serotonin (5-HT) transporters (SERT) and receptors. This study focuses on the in vitro and in vivo effects of modifying the amino-group of three N, N-dialkyl-substituted 5-MeO-tryptamines, namely 5-MeO-MET, 5-MeO-MiPT and 5-MeO-EiPT. The rank order of affinity at the human 5-HT1A and 5-HT2A receptors was 5-MeO-MET>5-MeO-MiPT>5-MeO-EiPT. Contrarily, for the human SERT, 5-MeO-EiPT showed the highest affinity, followed by 5-MeO-MiPT and 5-MeO-MET.
Moreover, the order of potency inhibiting 5-HT uptake was in accordance with the Ki values for SERT. Overall, 5-MeO-tryptamines with bulkier N, N-dialkyl groups present more affinity at blocking SERT, whereas reducing the alkyl chain on the amino group increases the affinity for both 5-HT1A and 5-HT2A receptors. Additionally, studies examined in mice whether these substances induce the head-twitch response (HTR), a 5-HT2A receptor mediated response that is widely used as a behavioral proxy for hallucinogen effects in humans. Furthermore, 5-HT2A (ketanserin) and 5-HT1A (WAY100135) antagonists and MAO inhibitor (harmaline) were also administered before 5-MeO-tryptamine injection, and HTRs were also analyzed. Our results demonstrate that 5-MeO-MET has the highest efficacy inducing HTR, which correlates with the higher affinity for 5-HT1A and 5-HT2A receptors. Moreover, these findings demonstrate that 5-HT1A receptor inactivation increases the HTR induced by hallucinogenic 5-MeO-tryptamines administration, revealing the opposite role of 5-HT1A and 5-HT2A receptors. It has also been known that there is an inter-relationship between the central 5-HT system and thermoregulatory mechanisms in many species, including rodents and humans. Activation of the 5-HT1A receptor in rodents results in the reduction in core body temperature. During this study it has been observed that more bulkier tryptamines seems to provoke a more drastic decrease of core temperature in mice.
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