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. 2024 Mar 1:245:109827.
doi: 10.1016/j.neuropharm.2023.109827. Epub 2023 Dec 27.

Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones

Lauren R Fitzgerald  1 , Brenda M Gannon  1 , Donna Walther  2 , Antonio Landavazo  3 , Takato Hiranita  4 , Bruce E Blough  3 , Michael H Baumann  2 , William E Fantegrossi  5
Affiliations

Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones

Lauren R Fitzgerald et al. Neuropharmacology. .

Abstract

Substitutions to the phenethylamine structure give rise to numerous amphetamines and cathinones, contributing to an ever-growing number of abused novel psychoactive substances. Understanding how various substitutions affect the pharmacology of phenethylamines may help lawmakers and scientists predict the effects of newly emerging drugs. Here, we established structure-activity relationships for locomotor stimulant and monoamine transporter effects of 12 phenethylamines with combinations of para-chloro, β-keto, N-methyl, or N-ethyl additions. Automated photobeam analysis was used to evaluate effects of drugs on ambulatory activity in mice, whereas in vitro assays were used to determine activities at transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT) in rat brain synaptosomes. In mouse studies, all compounds stimulated locomotion, except for 4-chloro-N-ethylcathinone. Amphetamines were more potent stimulants than their β-keto counterparts, while para-chloro amphetamines tended to be more efficacious than unsubstituted amphetamines. Para-chloro compounds also produced lethality at doses on the ascending limbs of their locomotor dose-effect functions. The in vitro assays showed that all compounds inhibited uptake at DAT, NET, and SERT, with most compounds also acting as substrates (i.e., releasers) at these sites. Unsubstituted compounds displayed better potency at DAT and NET relative to SERT. Para-chloro substitution or increased N-alkyl chain length augmented relative potency at SERT, while combined para-chloro and N-ethyl substitutions reduced releasing effects at NET and DAT. These results demonstrate orderly SAR for locomotor stimulant effects, monoamine transporter activities, and lethality induced by phenethylamines. Importantly, 4-chloro compounds produce toxicity in mice that suggests serious risk to humans using these drugs in recreational contexts.

Keywords: Amphetamine; Cathinone; Structure activity relationship.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: William Fantegrossi reports financial support and equipment, drugs, or supplies were provided by US Department of Justice. Lauren Fitzgerald reports financial support was provided by National Institutes of Health. Michael Baumann reports financial support was provided by National Institute on Drug Abuse Intramural Research Program. Bruce Blough reports financial support was provided by National Institute on Drug Abuse.

Figures

Figure 1:
Figure 1:. Structures
Array of 12 compounds where the structures become increasingly complex, differing from one another by either a para-chlorine substitution, β-keto substitution, or N-methyl or N-ethyl substitution. The top row includes amphetamine (AMP), methamphetamine (METH), and ethamphetamine (EA). The second row depicts the para-chlorinated compounds of row 1, including 4-Cl amphetamine (4CA), 4-Cl methamphetamine (4CMA), and 4-Cl ethamphetamine (4CEA), respectively. Similarly, the third row contains cathinone (CATH), methcathinone (MC), and ethcathinone (EC), and the fourth row contains 4-Cl cathinone (4CC), 4-Cl methcathinone (4CMC), and 4-Cl ethcathinone (4CEC). Within each row, columns 2 and 3 contain the N-methyl and N-ethyl substituted analogue of column 1, respectively. The third and fourth rows depict the β-ketone containing analogues of the first and second rows, respectively.
Figure 2:
Figure 2:. Ambulatory Distance
Average locomotor activity over 6 h ± SEM elicited by IP administration of saline (open circles) or the given dose of the specified drug (filled squares). Abscissa: ‘Saline’ represents saline control data and numbers refer to dose of the respective drug expressed as mg/kg on a log scale. Each point represents a separate group of animals; n = 8. Ordinate: mean distance traveled in meters recorded over 6 hours post injection. Asterisks indicate a significant difference (p<0.05) between dose administered and saline using a one-way ANOVA. Octothorpes indicate a significant difference (p<0.05) between dose administered and next lowest dose administered.
Figure 3:
Figure 3:. In Vitro Assays
Panel A illustrates the effects of the test drugs on inhibition of [3H]neurotransmitter uptake by DAT (white circles), NET (gray squares), or SERT (black triangles) in rat brain tissue. Abscissa: molar drug concentration. Ordinate: percent of maximal uptake expressed as mean ± SD for n=3 experiments performed in triplicate. Panel B depicts the effects of the test drugs on release of [3H]MPP+ at DAT (white circles) and NET (gray squares), or [3H]5-HT at SERT (black triangles) in rat rain tissue. Abscissa: molar drug concentration. Ordinate: percent of maximal release expressed as mean ± SD for n=3 experiments performed in triplicate.
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