Neurochemical and Cardiovascular Effects of 4-Chloro Ring-Substituted Synthetic Cathinones in Rats

Abstract

Synthetic cathinones are a class of new psychoactive substances that display psychomotor stimulant properties, and novel cathinone analogs continue to emerge in illicit drug markets worldwide. The aim of the present study was to characterize the pharmacology of 4-chloro ring-substituted cathinones that are appearing in illicit drug markets, as compared to the effects of 4-methylmethcathinone (mephedrone).Synaptosomes were prepared from rat caudate for dopamine transporter (DAT) assays, or from whole brain minus caudate and cerebellum for norepinephrine transporter (NET) and serotonin transporter (SERT) assays. Findings from transporter uptake inhibition and release assays showed that mephedrone and 4-chloromethcathinone (4-CMC) function as substrates at DAT, NET, and SERT, with similar potency at all three transporters. In contrast, 4-chloro-α-pyrrolidinopropiophenone (4-CαPPP) was an uptake inhibitor at DAT and NET, with similar potency at each site, but had little activity at SERT. 4-Chloroethcathinone (4-CEC) was a low potency uptake inhibitor at DAT and NET but a substrate at SERT. In rats implanted with telemetry transmitters, mephedrone and 4-CMC increased blood pressure, heart rate, and locomotor activity to a similar extent. 4-CEC and 4-CαPPP were less potent at increasing blood pressure and had modest stimulatory effects on heart rate and activity. 4-CMC also transiently decreased temperature at the highest dose tested. All three 4-chloro ring-substituted cathinones are biologically active, but only 4-CMC has potency comparable to mephedrone.Collectively, our findings suggest that 4-CMC and other 4-chloro cathinones may have abuse potential and adverse effects in humans that are analogous to those associated with mephedrone.

Bath Salts to Therapies: Can Separation of Adverse and Therapeutic Effects of Substituted Cathinones Lead to a Medication for Psychostimulant Use Disorder?

“…In summary, the findings of Chojnacki et al (2023) shed important new light on the pharmacology of 4-chloro ring-substituted cathinones and emphasize the translational importance of identifying cathinones with enhanced SERT and NET potency relative to DAT. This scientific research raises hope that through a combination of different strategies, such as increasing the size of 4-position ring substitutions or enantiomeric separation of addictive and therapeutic properties (Philogene-Khalid et al, 2017), an effective and safe, cathinone-based therapeutic for psychostimulant use disorder could be identified.…”

“…Some cathinones act as substrates at monoamine transporters and promote release (similar to amphetamine), whereas others act as blockers of the monoamine transporters (similar to cocaine). In their current study, Chojnacki et al (2023) investigated the pharmacological mechanisms of three 4-chloro ring-substituted cathinones in comparison with mephedrone. Because of the known cardiotoxic effects of the synthetic cathinones, they also investigated these compounds on blood pressure, heart rate, and body temperature in male rats.…”

“…Bupropion does lack efficacy against cocaine use disorders in clinical trials (Margolin et al, 1995;Kampman, 2008). However, compared with 4-CMC and the 4-chlorocathinones characterized by Chojnacki et al (2023), bupropion has a mechanistic profile that is quite different, most notably the negligible effects on SERT and serotonin transmission (DeBattista, 2022). In the present article, Chojnacki et al (2023) showed that 4-chloro ring-substituted cathinones are active and produce effects that are pharmacologically similar to mephedrone.…”

“…However, compared with 4-CMC and the 4-chlorocathinones characterized by Chojnacki et al (2023), bupropion has a mechanistic profile that is quite different, most notably the negligible effects on SERT and serotonin transmission (DeBattista, 2022). In the present article, Chojnacki et al (2023) showed that 4-chloro ring-substituted cathinones are active and produce effects that are pharmacologically similar to mephedrone. In the context of drug discovery, one approach is to focus on characterization of 4-position ring substitutions to discriminate therapeutic and addictive effects.…”

“…In this issue of the Journal of Pharmacology and Experimental Therapeutics, Chojnacki et al (2023), at the National Institutes on Drug Abuse and Alcohol Abuse and Alcoholism, report on the pharmacology of 4-chloro ring-substituted cathinones. One of these, 4-chloromethcathinone (4-CMC), is associated with significant toxicities and deaths in human users (Tomczak et al, 2018;La Maida et al, 2021).…”