Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs

Abstract

Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure—activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters.

Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats

“…Additionally, the relative potencies of these drugs to facilitate ICSS were similar to their relative potencies to increase NAc DA levels, supporting a role for NAc DA in mediating ICSS facilitation by these compounds. Both cocaine and methamphetamine also dosedependently increased NAc 5-HT levels, and we and others have reported previously that either increases in 5-HT levels or activation of some 5-HT receptors (e.g., 5-HT2C receptors) can depress baseline ICSS and oppose DA-mediated ICSS facilitation and other stimulant effects [37][38][39][40]. However, this type of behavioral depression is usually associated with relatively large increases in NAc 5-HT levels (i.e., >400%; [5,40]).…”

“…First, amphetamine-maintenance effects were compared on ICSS facilitation produced by cocaine, MDPV, and methamphetamine. Second, ICSS facilitation by monoamine transporter ligands correlates with selectivity to increase DA vs. 5-HT levels in NAc [5,24]. Accordingly, we also used in vivo microdialysis to compare amphetamine-maintenance effects on cocaine-, MDPV-, and methamphetamine-induced changes in NAc DA and 5-HT levels.…”

The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter

“…Instead, it has been hypothesized that the relative reinforcing effectiveness of drugs that interact with monoamine transporters is influenced by not only their actions at DAT but also at SERT [22,24,34,35]. Indeed, consistent evidence from studies using analogs of cocaine and amphetamine with increased SERT activity, or mixtures of amphetamine and fenfluramine, suggests that reducing selectivity for DAT relative to SERT results in drugs that are less effective reinforcers than cocaine or amphetamine [22,24,36].…”

Effects of repeated treatment with methcathinone, mephedrone, and fenfluramine on intracranial self-stimulation in rats

“…We have shown previously that levels of abuse-related ICSS facilitation produced by some synthetic cathinones and other monoamine transporter ligands in ICSS are governed in part by their relative potency to act at DAT vs. SERT (Bauer et al 2013;Negus and Banks 2017). For example, DAT>SERT-selective transporter substrates (e.g.…”