Evaluation of the abuse potential of AM281, a new synthetic cannabinoid CB₁ receptor antagonist

Botanas, C.J.,de la Pena, J.B.,dela Pena, I.J.,Tampus, R.,Kim, H.J.,Yoon, S.S.,Seo, J.W.,Jeong, E.J.,Cheong, J.H. North-Holland ; Elsevier Science Ltd 2015 european journal of pharmacology Vol.766 No.-

AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) is a new synthetic cannabinoid CB<SUB>1</SUB> receptor antagonist. Similar to other cannabinoid antagonists, AM281 has been suggested to have therapeutic indications. However, recent reports have suggested that cannabinoid CB<SUB>1</SUB> receptor antagonists may share similar behavioral effects with other drugs of abuse such as cocaine and amphetamine. These reports cast doubts on the safety profile of AM281. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of AM281 through two of the most widely used animal models for assessing the abuse potential of drugs: the conditioned place preference (CPP) and self-administration (SA) tests. Experiments were performed in Sprague-Dawley rats in various dosages [CPP (0.1, 0.5 or 2.5mg/kg), SA (0.005, 0.025 or 0.1mg/kg/infusion)]. We also delved into the consequences of repeated drug exposure on the subsequent response to the drug. Thus, parallel experiments were carried out in rats pretreated with AM281 for 7 or 14 days. Our findings indicated that AM281, at any dose, did not induce CPP and SA in drug-naive rats. Interestingly, significant CPP (0.5mg/kg of AM281), but not SA, was observed in 14 days pretreated rats. These observations suggest that AM281 per se has no or minimal rewarding and reinforcing properties, but alterations in neuronal functions and behavior due to repeated AM281 exposure may contribute in part to the abuse potential of this drug. In view of this finding, we advocate the careful use, monitoring, and dispensation of AM281.

Methoxetamine: A foe or friend?

Botanas, Chrislean Jun,de la Peñ,a, June Bryan,Kim, Hee Jin,Lee, Yong Sup,Cheong, Jae Hoon Elsevier 2019 Neurochemistry International Vol.122 No.-

<P><B>Abstract</B></P> <P>Methoxetamine (MXE) is an <I>N</I>-methyl-D-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to other dissociative substances, such as ketamine and phencyclidine. There are reports on the misuse of MXE, which sometimes resulted in adverse consequences and death. Studies have also shown that MXE has abuse liability and stimulates dopamine neurotransmission in the mesolimbic reward pathway in the brain. These findings have contributed to the negative impression on MXE. However, recent preclinical studies have identified the antidepressant properties of MXE, which are attributed to its ability to affect the glutamatergic and serotonergic systems. MXE is also reported to have analgesic effects. These findings show some of the “redeeming qualities” of MXE and indicate its possible therapeutic uses. In this paper, we have reviewed the findings that provide insights into the adverse and potential therapeutic effects of MXE. We compiled studies on the toxicity, psychotomimetic effects, and abuse liability of MXE, as well as its promising antidepressant and analgesic properties. We also have discussed the mechanism of action that might mediate the somewhat paradoxical effects observed. Importantly, this review provides valuable information on MXE for future research and will enable a better understanding of its psychopharmacological properties and the mechanisms responsible for its unique effects.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We review the adverse and potential therapeutic effects of methoxetamine (MXE). </LI> <LI> MXE, a structural analogue of ketamine, is an NMDA receptor antagonist. </LI> <LI> MXE produces toxic and dissociative effects and has abuse liability. </LI> <LI> MXE also has antidepressant and analgesic properties like ketamine. </LI> <LI> MXE can affect the dopaminergic, glutamatergic, and serotonergic system. </LI> </UL> </P>

Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms

Botanas, Chrislean Jun,Bryan de la Peñ,a, June,Custodio, Raly James,Joy dela Peñ,a, Irene,Kim, Mikyung,Woo, Taeseon,Kim, Hee Jin,Kim, Hye In,Chang Cho, Min,Lee, Yong Sup,Cheong, Jae Hoon Pergamon Press 2017 Neuropharmacology Vol.126 No.-

<P><B>Abstract</B></P> <P>Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MXE produced rapid and sustained antidepressant effects. </LI> <LI> Antidepressant effects MXE were blocked by NBQX, an AMPA receptor antagonist. </LI> <LI> Ketanserin, a 5HT2 receptor antagonist, attenuated antidepressant effects of MXE. </LI> <LI> MXE altered hippocampal glutamatergic and serotonergic-related gene expression. </LI> <LI> MXE's effects likely mediated by glutamertergic and serotonergic systems. </LI> </UL> </P>

The Abuse Potential of α-Piperidinopropiophenone (PIPP) and α-Piperidinopentiothiophenone (PIVT), Two New Synthetic Cathinones with Piperidine Ring Substituent

Botanas, Chrislean Jun,Yoon, Seong Shoon,de la Pena, June Bryan,dela Pena, Irene Joy,Kim, Mikyung,Woo, Taeseon,Seo, Joung-Wook,Jang, Choon-Gon,Park, Kyung-Tae,Lee, Young Hun,Lee, Yong Sup,Kim, Hee Jin The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.2

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) ${\alpha}-piperidinopropiophenone$ (PIPP) and (2) ${\alpha}-piperidinopentiothiophenone$ (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.

The Abuse Potential of α-Piperidinopropiophenone (PIPP) and α-Piperidinopentiothiophenone (PIVT), Two New Synthetic Cathinones with Piperidine Ring Substituent

( Chrislean Jun Botanas ),( Seong Shoon Yoon ),( June Bryan De La Pena ),( Irene Joy Dela Pena ),( Mikyung Kim ),( Taeseon Woo ),( Joung-wook Seo ),( Choon-gon Jang ),( Kyung-tae Park ),( Young Hun Le 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.2

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) α-piperidinopropiophenone (PIPP) and (2) α-piperidinopentiothiophenone (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.

Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

Custodio, Raly James Perez,Botanas, Chrislean Jun,Yoon, Seong Shoon,de la Pena, June Bryan,dela Pena, Irene Joy,Kim, Mikyung,Woo, Taeseon,Seo, Joung-Wook,Jang, Choon-Gon,Kwon, Yong Ho,Kim, Nam Yong,Le The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

Overexpression of the Thyroid Hormone-Responsive (THRSP) Gene in the Striatum Leads to the Development of Inattentive-like Phenotype in Mice

Custodio, Raly James Perez,Botanas, Chrislean Jun,de la Peñ,a, June Bryan,dela Peñ,a, Irene Joy,Kim, Mikyung,Sayson, Leandro Val,Abiero, Arvie,Ryoo, Zae Young,Kim, Bung-Nyun,Kim, Hee Jin,C Elsevier 2018 NEUROSCIENCE Vol.390 No.-

<P><B>Abstract</B></P> <P>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 8–12% of children globally. Factor analyses have divided ADHD symptoms into two domains: inattention and a combination of hyperactivity and impulsivity. The identification of domain-specific genetic risk variants may help uncover potential genetic mechanisms underlying ADHD. We have previously identified that thyroid hormone-responsive (THRSP) gene expression is upregulated in spontaneously hypertensive rats (SHR/NCrl) and Wistar-Kyoto (WKY/NCrl) rats which exhibited inattention behavior. Thus, we established a line of THRSP overexpressing (OE) mice and assessed their behavior through an array of behavioral tests. The gene and protein overexpression of THRSP in the striatum (STR) was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The THRSP OE mice exhibited inattention in the novel-object recognition and Y-maze test, but not hyperactivity in the open-field test and impulsivity in the cliff-avoidance and delay-discounting task. We have also found that expression of dopamine-related genes (dopamine transporter, tyrosine hydroxylase, and dopamine D1 and D2 receptors) in the STR increased. Treatment with methylphenidate (5 mg/kg), the most commonly used medication for ADHD, improved attention and normalized expression levels of dopamine-related genes in THRSP OE mice. Our findings suggest that THRSP plays a role in the inattention phenotype of ADHD and that the THRSP OE mice may be used as an animal model to elucidate the genetic mechanisms of the disorder.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Thyroid-hormone responsive (THRSP) overexpressing (OE) mice exhibits inattention, but not hyperactivity and impulsivity. </LI> <LI> THRSP OE mice have elevated striatal dopamine-related gene (DAT, TH, and dopamine D1 and D2 receptors) expression levels. </LI> <LI> Methylphenidate improves attention in THRSP OE mice. </LI> <LI> Methylphenidate normalizes the expression levels of dopaminergic-related genes in the striatum of THRSP OE mice. </LI> <LI> THRSP OE mice can be a potential mouse model for ADHD-inattentive type. </LI> </UL> </P>

Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

Raly James Perez Custodio,Chrislean Jun Botanas,윤성순,June Bryan de la Peña,Irene Joy dela Peña,김미경,우태선,서정욱,장춘곤,권용호,김남용,이용섭,김희진,정재훈 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

Catalpol and Mannitol, Two Components of Rehmannia glutinosa, Exhibit Anticonvulsant Effects Probably via GABAA Receptor Regulation

( Mikyung Kim ),( Srijan Acharya ),( Chrislean Jun Botanas ),( Raly James Custodio ),( Hyun Jun Lee ),( Leandro Val Sayson ),( Arvie Abiero ),( Yong Soo Lee ),( Jae Hoon Cheong ),( Kyeong-man Kim ),( 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.2

Epilepsy is a brain disorder that affects millions of people worldwide and is usually managed using currently available antiepileptic drugs, which result in adverse effects and are ineffective in approximately 20-25% of patients. Thus, there is growing interest in the development of new antiepileptic drugs with fewer side effects. In a previous study, we showed that a Rehmannia glutinosa (RG) water extract has protective effects against electroshock- and pentylenetetrazol (PTZ)-induced seizures, with fewer side effects. In this study, the objective was to identify the RG components that are responsible for its anticonvulsant effects. Initially, a number of RG components (aucubin, acteoside, catalpol, and mannitol) were screened, and the anticonvulsant effects of different doses of catalpol, mannitol, and their combination on electroshock- and chemically (PTZ or strychnine)-induced seizures in mice, were further assessed. Gamma-aminobutyric acid (GABA) receptor binding assay and electroencephalography (EEG) analysis were conducted to identify the potential underlying drug mechanism. Additionally, treated mice were tested using open-field and rotarod tests. Catalpol, mannitol, and their combination increased threshold against electroshock-induced seizures, and decreased the percentage of seizure responses induced by PTZ, a GABA antagonist. GABA receptor binding assay results revealed that catalpol and mannitol are associated with GABA receptor activity, and EEG analysis provided evidence that catalpol and mannitol have anticonvulsant effects against PTZ-induced seizures. In summary, our results indicate that catalpol and mannitol have anticonvulsant properties, and may mediate the protective effects of RG against seizures.

Evaluation of the Abuse Potential of Novel Amphetamine Deriva-tives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

( Raly James Perez Custodio ),( Chrislean Jun Botanas ),( Seong Shoon Yoon ),( June Bryan De La Pena ),( Irene Joy Dela Pena ),( Mikyung Kim ),( Taeseon Woo ),( Joung-wook Seo ),( Choon-gon Jang ),( Y 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.