Locomotor Effects of Substituted Amphetamines and Cathinones in Mice: Structure‐Activity Relationships

Abstract

Substituted amphetamines represent one of the largest and most pharmacologically‐diverse classes of abused drugs. Modifications to the amphetamine base structure are seemingly limitless, and novel psychoactive substituted amphetamines continuously emerge on the illicit market. Amphetamine analogues containing a ketone at the beta carbon are referred to as cathinones, which are typically the active constituents in abused “bath salts” products. Each “generation” of cathinone analogues introduces new structural motifs, most likely in response to regulatory control of previous compounds. One recently identified “bath salts” constituent is 4‐chloroethcathinone (4‐CEC), consisting of the base amphetamine structure with the addition of an ethyl side chain, a chlorine at the 4‐position, and a ketone group at the beta carbon. In these studies, we compared 12 structurally‐analogous substituted amphetamines and cathinones increasing in structural complexity from amphetamine to 4‐CEC in order to assess structure‐activity relationships for locomotor stimulant and toxic effects in mice. Automated photobeam chambers were used to record various aspects of mouse locomotor activity including jump count, time in stereotypy, vertical time, speed, and distance. Full dose‐effect curves were determined for each compound, starting with a dose that produced saline‐like distance traveled, and increasing in half‐log units until distance decreased from that drug's peak, or until lethal effects were observed. For the substituted amphetamines, increasing the length of the side chain increased maximal effectiveness on locomotor endpoints. As compared to analogous unsubstituted compounds, addition of a chlorine at the 4‐position did not substantially impact distance traveled, but increased time spent in stereotypy. These same trends were also observed with the substituted cathinones. Interestingly, 4‐CEC produced lethality in all subjects at doses on the ascending limb of the dose‐effect curve for distance traveled. Further development of structure‐activity relationships for these drugs may determine which moieties of their chemical structures are involved in producing specific pharmacological effects, and may allow predictions about abuse liability or toxic effects of new pharmacological entities with similar structural motifs.Support or Funding InformationThese studies supported by DA022981, R01‐DA039195, and DEA/FDA HHSF223201610079C.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.