The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes

Abstract

Rationale.-Novel synthetic 'bath salt' cathinones continue to appear on the street as abused and addictive drugs. The range of subjective experiences produced by different cathinones suggests that some compounds have primarily dopaminergic activity (possible stimulants) while others have primarily serotonergic activity (possible empathogenics). An understanding of the structure activity relationships (SARs) of these compounds will help in assessing the likely behavioral effects of future novel structures, and to define potential therapeutic strategies to reverse any reinforcing effects. Objectives.-A series of methcathinone analogues was systematically studied for their activity at the dopamine and serotonin transporters. Compound structures varied at the aromatic group, either by substituent or by replacement of the phenyl ring with a naphthalene or indole ring. Methods.-A novel, high yielding synthesis of methcathinone hydrochlorides was developed which avoids isolation of the unstable free bases. Neurotransmitter transporter release activity was determined in rat brain synaptosomes as previously reported. Compounds were also screened for activity at the norepinephrine transporter. Results.-Twenty-eight methcathinone analogs were analyzed and fully characterized in dopamine and serotonin transporter release assays. Compounds substituted at the 2-position (ortho) were primarily dopaminergic. Compounds substituted at the 3-position (meta) were found to be much less dopaminergic, with some substituents favoring serotonergic activity. Compounds substituted at the 4position (para) were found to be far more serotonergic, as were disubstituted compounds and other large aromatic groups. One exception was the fluoro substituted analogs which seem to favor the dopamine transporter. Conclusions.-The dopaminergic to serotonergic ratio can be manipulated by choice of substituent and location on the aromatic ring. It is therefore likely possible to tweak the subjective *

Four Synthetic Cathinones: 3-Chloromethcathinone, 4-Chloromethcathinone, 4-Fluoro-α-Pyrrolidinopentiophenone, and 4-Methoxy-α-Pyrrolidinopentiophenone Produce Changes in the Spontaneous Locomotor Activity and Motor Performance in Mice with Varied Profiles

“…Therefore, although it is widely accepted that in rats compounds with high DAT selectivity are potent forward locomotor stimulators (Baumann et al 2011;Blough et al 2019), our data suggest that vertical locomotor activity in mice could be Effects of c 3-CMC (100-300 μM) and f 4-CMC (100-300 μM) on the integrity of cell membranes after 48-h incubation measured with LDH test. Data presented as mean ± standard error of the mean (SEM) from at least 3 independent experiments and expressed as a percentage of positive control group considered 100% cytotoxicity.…”

“…Assessment of the ability of drugs of abuse to increase spontaneous locomotor activity of rodents is an important tool to predict their abuse liability, as it is recognized that both reinforcing/rewarding properties are mediated by an increase of DA-ergic neurotransmission in the striatum, which is also manifested in the locomotor stimulation (Baumann et al 2011;Blough et al 2019;Bonano et al 2015). Therefore, it is recommended that any CNS-active drug should be evaluated for its abuse potential both using in vitro and in vivo pharmacological models (FDA 2017;Mdege et al 2017).…”

“…7c), and at mg/kg were markedly less active than either 4-F-PVP or 4-MeO-PVP ( Fig. 7d) (Blough et al 2019;Bonano et al 2015;Eshleman et al 2017).…”

Locomotor activity and discriminative stimulus effects of five novel synthetic cathinone analogs in mice and rats

“…Clephedrone (4-Chloromethcathinone; 4-CMC) is a monoamine transporter substrate (releaser) similar potency for SERT and DAT (Blough et al, 2018;Eshleman et al, 2013;2017), although one study reported that clephedrone was 3-fold more potent at releasing dopamine than serotonin, with equal efficacy (Bonano et al, 2015). However, when looking at time course, it is interesting to note that whereas clephedrone produced a large increase in DA levels, the onset was slow (Suyama et al, 2016).…”

Green Analysis of the Bromination Reaction of Propiophenone Derivatives Mediated by Cu2+ Complexes

“…On the other hand, ketones like propiophenone and its derivatives are important drug precursors . These compounds can generate many structures from brominated intermediates and then by the substitution for another building block or functional group.…”