In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones

Abstract

Overall, these studies aimed to understand structure-activity relationships (SAR) for behavioral endpoints of abused phenylethylamine analogues in mice.

The first experiments assessed monoamine transporter interactions in vitro and locomotor stimulant effects in vivo across a 12-compound series of amphetamines and cathinones. β-ketone addition decreased maximal distance traveled and impaired potency to inhibit uptake at dopamine, norepinephrine, and serotonin transporters, while 4-Cl addition increased distance traveled and elicited lethality on the ascending limb of locomotor dose-effect curves, likely related to increased serotonin in the synapse caused by these chlorinated compounds improved potency to inhibit SERT uptake and stimulate release through SERT.

The second studies aimed to determine the impact of a 3,4-methylenedioxy ring moiety on mediation of locomotor activity and place conditioning by an elevated ambient temperature for 4 structurally related psychostimulants: methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), α-pyrrolidinopentiophenone (αPVP), and 3,4-methylenedioxypyrovalerone (MDPV). All compounds elicited dose dependent locomotor stimulation and place preference at room temperature. In the elevated temperature, the 3,4-methylenedioxy containing compounds produced sensitization to stereotypy and attenuation of place preference, effects not obtained with METH or αPVP. For these two compounds—which lack the 3,4-methylenedioxy ring—place preference was potentiated at the elevated temperature.

The final studies evaluated the effects of running wheel access on basal temperature and locomotor stimulant effects of the above 4-compound series. Actively wheel running acutely increased core temperature above the species-typical range in mice. Additionally, wheel running access influenced the locomotor effects of at least one dose of METH, αPVP, and MDPV, indicating that wheel running availability might interact with locomotor stimulant effects in unpredictable ways.

Taken together, these studies demonstrate that orderly SAR can be established for individual and combined moiety substitutions among substituted amphetamines and substituted cathinones. Furthermore, parametrically determining the effects of differences in husbandry conditions for rodents will allow data to be utilized across institutions when establishing SAR. Systematically determining SAR in a reproducible way will increase the rate of abuse potential assessment for emerging novel psychoactive drugs, focusing scientific attention on particularly dangerous compounds and allowing legislators to implement public health policies in a more efficient manner.