Structure-Activity Relationships of Synthetic Cathinones

Abstract

Until recently, there was rather little interest in the structure-activity relationships (SARs) of cathinone analogs because so few agents were available, and because they represented a relatively minor drug abuse problem. Most of the early SAR was formulated on the basis of behavioral (e.g. locomotor and drug discrimination) studies using rodents. With the emergence on the clandestine market in the last few years of a large number of new cathinone analogs, termed “synthetic cathinones”, and the realization that they likely act at dopamine, norepinephrine, and/or serotonin transporters as releasing agents (i.e., as substrates) or reuptake inhibitors (i.e., as transport blockers), it has now become possible to better examine their SAR, and even their quantitative SAR (QSAR), in a more effective and systematic manner. An SAR picture is beginning to emerge and key structural features, such as the nature of the terminal amine, the size of the α substituent, stereochemistry, and the presence and position of aromatic substituents, are being found to impact action (i.e., as releasing agents or reuptake inhibitors) and transporter selectivity.

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

“…Pentylone, conversely, has been described as an uptake inhibitor 5 to 8-fold selective for DAT over SERT (Costa et al 2018;Eshleman et al 2018), a nonselective uptake inhibitor (Eshleman et al, 2017), a "hybrid" compound (Simmler et al, 2014;Saha et al, 2018), or a weak DAT/ SERT substrate (Dolan et al, 2018). Previous analyses of structure-activity relations among synthetic cathinones have demonstrated that tertiary amine substitution (as in dimethylone and dibutylone) or substitution with larger alkyl groups (as in ethylone or N-ethylpentylone) confers transporter-blocking properties to compounds (Kolanos et al, 2013;Solis, 2017;Glennon and Dukat, 2017), so the unstudied compounds currently under investigation potentially have more-prominent transporter-blockade effects relative to their mono-and methyl-substituted counterparts.…”

The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The “Phenylalkylaminome” with a Focus on Selected Drugs of Abuse

“…By “mixing and matching” the various substituents, certain cathinone analogs could possess “mixed” or “hybrid” actions. 75 This, once again, underscored the concept that small structural alterations to the phenylalkylamine scaffold can have a significant impact on pharmacology.…”

“…Bath salts was initially a combination of methylone (MDMC; 59 ) – the β-keto analog of MDMA ( 43 ), mephedrone ( 60 ), methylenedioxypyrovalerone (MDPV; 61 ; Figure 13), or one or more of these agents in combination with other (known or novel) phenylisopropylamines (reviewed 74,75 ).Today, the term “bath salts” is often used rather generically to refer to almost any synthetic cathinone. Over the past 5 or 6 years, approximately 150 different synthetic cathinones have been confiscated from the clandestine market.…”

“…Over the past 5 or 6 years, approximately 150 different synthetic cathinones have been confiscated from the clandestine market. 75 …”

“…Several SAR and QSAR studies have been reported for the synthetic cathinones (reviewed 75 ). With regard to those that behaved as releasing agents, the 4-position substituent determined selectivity for DAT vesus SERT.…”