Methcathinone: A new and potent amphetamine-like agent

Glennon, Richard A.; Yousif, Mamoun; Naiman, Noreen; Kalix, Peter

doi:10.1016/0091-3057(87)90164-x

Cited by 118 publications

(93 citation statements)

References 9 publications

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“…none; that is, from a structural perspective, methcathinone is to cathinone what methamphetamine is to amphetamine (Glennon et al, 1987). We examined S-(Ϫ)-cathinone and S-(Ϫ)-methcathinone for comparison with the phenylpropanolamines.…”

Section: S-(ϫ)-methcathinone Is the N-methyl Analog Of S-(ϫ)-cathi-mentioning

confidence: 99%

In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates

Rothman¹,

Vu²,

Partilla³

et al. 2003

J Pharmacol Exp Ther

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170

143

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Ephedrine is a long-studied stimulant available both as a prescription and over-the-counter medication, as well as an ingredient in widely marketed herbal preparations, and is also used as a precursor for the illicit synthesis of methamphetamine. Ephedrine is related to phenylpropanolamine, a decongestant removed from the market place due to concerns that its use increased the risk of hemorrhagic stroke. Standard pharmacology texts emphasize that ephedrine is both a direct and indirect adrenergic agonist, activating adrenergic receptors both by direct agonist activity as well as by releasing norepinephrine via a carrier-mediated exchange mechanism. Chemically, ephedrine possesses two chiral centers. In the present study, we characterized the stereoisomers of ephedrine and the closely related compounds pseudoephedrine, norephedrine, pseudonorephedrine (cathine), methcathinone, and cathinone at biogenic amine transporters and a large battery of cloned human receptors (e.g., "receptorome"). The most potent actions of ephedrine-type compounds were as substrates of the norepinephrine transporter (EC 50 values of about 50 nM) followed by substrate activity at the dopamine transporter. Screening the receptorome demonstrated weak affinity at ␣ 2 -adrenergic and 5-hydroxytryptamine 7 receptors (K i values 1-10 M) and no significant activity at ␤-adrenergic or ␣ 1 -adrenergic receptors. Viewed collectively, these data indicate that the pharmacological effects of ephedrine-like phenylpropanolamines are likely mediated by norepinephrine release, and although sharing mechanistic similarities with, they differ in important respects from those of the phenylpropanonamines methcathinone and cathinone and the phenyisopropylamines methamphetamine and amphetamine.

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Section: S-(ϫ)-methcathinone Is the N-methyl Analog Of S-(ϫ)-cathi-mentioning

confidence: 99%

In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates

Rothman¹,

Vu²,

Partilla³

et al. 2003

J Pharmacol Exp Ther

Self Cite

170

143

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“…Routine drugs of abuse screenings do not allow the detection of MPPP in biosamples (Springer et al, 2002). Although little information about its pharmacological and toxicological properties is available, amphetamine-like effects can be predicted, since structurally similar anorectics like amfepramone and metamfepramone, drugs of abuse like cathinone and methcathinone, and antidepressants like bupropion are based on this mode of action (Bryant et al, 1983;Kalix and Glennon, 1986;Glennon et al, 1987;Martinez et al, 1998). Possible clinical effects of MPPP include tachycardia, hypertension, mydriasis, and tremor.…”

mentioning

confidence: 99%

IDENTIFICATION OF CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 4′-Methyl-Α-Pyrrolidinopropiophenone, a NOVEL SCHEDULED DESIGNER DRUG, IN HUMAN LIVER MICROSOMES

Springer¹,

Paul²,

Staack³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:4 -Methyl-␣-pyrrolidinopropiophenone (MPPP) is a new drug of abuse. It is believed to have an abuse potential similar to that of amphetamines. Previous studies with Wistar rats had shown that MPPP was metabolized mainly by hydroxylation in position 4 followed by dehydrogenation to the corresponding carboxylic acid. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of MPPP to 4 -hydroxymethyl-pyrrolidinopropiophenone. Baculovirus-infected insect cell microsomes and human liver microsomes were used for this purpose. Only CYP2C19 and CYP2D6 catalyzed this hydroxylation. The apparent K m and V max values for the latter were 9.8 ؎ 2.5 M and 13.6 ؎ 0.7 pmol/min/pmol P450, respectively. 4Ј-Methyl-␣-pyrrolidinopropiophenone [MPPP 1 , international nonproprietary name: 2-(pyrrolidine-1-yl)-1-( p-tolyl)propane-1-one] is a new designer drug that has appeared on the illicit drug market. MPPP has been scheduled in the German Act of Controlled Substances after large amounts of tablets were distributed for recreational use and seized by the police (Roesner et al., 1999). Routine drugs of abuse screenings do not allow the detection of MPPP in biosamples (Springer et al., 2002). Although little information about its pharmacological and toxicological properties is available, amphetamine-like effects can be predicted, since structurally similar anorectics like amfepramone and metamfepramone, drugs of abuse like cathinone and methcathinone, and antidepressants like bupropion are based on this mode of action (Bryant et al., 1983;Kalix and Glennon, 1986;Glennon et al., 1987;Martinez et al., 1998). Possible clinical effects of MPPP include tachycardia, hypertension, mydriasis, and tremor.Previous in vivo studies in rats showed that MPPP was mainly metabolized by hydroxylation of the 4Ј-methyl group (Fig. 1) followed by dehydrogenation to the corresponding carboxylic acid (Springer et al., 2002). The aim of the study reported here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the hydroxylation and to determine the kinetic constants for this metabolic reaction. Materials and MethodsMaterials. MPPP-HCl and MDPPP-HCl (3Ј,4Ј-methylenedioxy-␣-pyrrolidinopropiophenone, international nonproprietary name: 1-(1,3-benzodioxol-5-yl)-2-(pyrrolidine-1-yl)propane-1-one) were provided by the Hessian State Criminal Office (Wiesbaden, Germany), before the compounds had entered the German Act of Controlled Substances. NADP ϩ was obtained from Biomol (Hamburg, Germany), isocitrate, and isocitrate dehydrogenase from Sigma (Taufkirchen, Germany), all other chemicals and reagents from Merck (Darmstadt, Germany). The following microsomes were purchased from NatuTec (Frankfurt/Main, Germany): baculovirus-infected insect cell microsomes containing 1 nmol/ml CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 (Supersomes), wild-type baculovirus-infecte...

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“…Methcathinone (MCAT) is the b-ketone analog of methamphetamine and serves as a parent compound to abused designer drugs that include mephedrone (4-CH 3 MCAT) and flephedrone (4-F MCAT) (Glennon et al, 1987;Spiller et al, 2011;De Felice et al, 2014). Like methamphetamine, MCAT functions as a monoamine transporter substrate that selectively promotes release of dopamine (DA) and norepinephrine over serotonin (5-HT) (Cozzi et al, 1999(Cozzi et al, , 2013Baumann et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Suyama

Sakloth

Kolanoś

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuserelated behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH 3, and 4-OCH 3 ) produced dose-and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r 5 0.89, P 5 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r 5 0.95, P , 0.01); and 3) molecular volume of the para substituent (r 5 20.85, P 5 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

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Methcathinone: A new and potent amphetamine-like agent

Cited by 118 publications

References 9 publications

In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates

In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates

IDENTIFICATION OF CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 4′-Methyl-Α-Pyrrolidinopropiophenone, a NOVEL SCHEDULED DESIGNER DRUG, IN HUMAN LIVER MICROSOMES

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

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