Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice
Arvie Abiero1,†, In Soo Ryu2,†, Chrislean Jun Botanas1, Raly James Perez Custodio1, Leandro Val Sayson1, Mikyung Kim1, Hyun Jun Lee1, Hee Jin Kim1, Joung-Wook Seo2, Min Chang Cho3, Kun Won Lee3, Sung Yeun Yoo3, Choon-Gon Jang4, Yong Sup Lee3,* and Jae Hoon Cheong1,*
1Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795,
2Center for Safety Pharmacology, Korea Institute of Toxicology, Daejeon 34114,
3Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447,
4Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
E-mail: kyslee@khu.ac.kr (Lee YS), cheongjh@syu.ac.kr (Cheong JH)
Tel: +82-2-961-0370 (Lee YS), +82-2-2339-1605 (Cheong JH)
Fax: +82-2-966-5586 (Lee YS), +82-2-2339-1619 (Cheong JH)
The first two authors contributed equally to this work.
Received: March 15, 2019; Revised: May 8, 2019; Accepted: May 23, 2019; Published online: June 24, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Tryptamines are monoamine alkaloids with hallucinogenic properties and are widely abused worldwide. To hasten the regulations of novel substances and predict their abuse potential, we designed and synthesized four novel synthetic tryptamine analogs: Pyrrolidino tryptamine hydrochloride (PYT HCl), Piperidino tryptamine hydrochloride (PIT HCl), N,N-dibutyl tryptamine hydrochloride (DBT HCl), and 2-Methyl tryptamine hydrochloride (2-MT HCl). Then, we evaluated their rewarding and reinforcing effects using the conditioned place preference (CPP) and self-administration (SA) paradigms. We conducted an open field test (OFT) to determine the effects of the novel compounds on locomotor activity. A head-twitch response (HTR) was also performed to characterize their hallucinogenic properties. Lastly, we examined the effects of the compounds on 5-HTR1a and 5-HTR2a in the prefrontal cortex using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. None of the compounds induced CPP in mice or initiated SA in rats. PYT HCl and PIT HCl reduced the locomotor activity and elevated the 5-HTR1a mRNA levels in mice. Acute and repeated treatment with the novel tryptamines elicited HTR in mice. Furthermore, a drug challenge involving a 7-day abstinence from drug use produced higher HTR than acute and repeated treatments. Both the acute treatment and drug challenge increased the 5-HTR2a mRNA levels. Ketanserin blocked the induced HTR. Taken together, the findings suggest that PYT HCl, PIT HCl, DBT HCl, and 2-MT HCl produce hallucinogenic effects via 5-HTR2a stimulation, but may have low abuse potential.
Keywords: Novel synthetic tryptamine analogs, Abuse potential, Conditioned place preference, Self-administration, Head-twitch response, 5-HT2 receptors


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