Structure-Activity Relationships for a Recently Controlled Synthetic Cathinone Dopamine Transporter Reuptake Inhibitor: α-Pyrrolidinohexiophenone (α-PHP).

HHS Public Access Author manuscript Author Manuscript ACS Chem Neurosci. Author manuscript; available in PMC 2024 July 19. Published in final edited form as: ACS Chem Neurosci. 2023 July 19; 14(14): 2527–2536. doi:10.1021/acschemneuro.3c00156. Structure-Activity Relationships for a Recently Controlled Synthetic Cathinone Dopamine Transporter Reuptake Inhibitor: α-Pyrrolidinohexiophenone (α-PHP) Rachel A. Davies1, Vy T. Nguyen2, Jose M. Eltit2,*, Richard A. Glennon1,* 1Department Author Manuscript of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University; Richmond, Virginia 23298 U.S. 2Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University; Richmond, Virginia 23298 U.S. Abstract Author Manuscript α-Pyrrolidinohexiophenone (α-PHP) is the one-carbon unit α-extended homolog of the betterknown and widely abused synthetic cathinone central stimulant α-PVP (“flakka”); both are now U.S. Schedule I controlled substances. Structurally, α-PVP and α-PHP possess a common terminal N-pyrrolidine moiety and differ only with respect to the length of their α-alkyl chain. Using a synaptosomal assay, we previously reported that α-PHP is at least as potent as α-PVP as a dopamine transporter (DAT) reuptake inhibitor. A systematic structure-activity study of synthetic cathinones (e.g. α-PHP) as DAT reuptake inhibitors (i.e., transport blockers), a mechanism thought responsible for their abuse liability, has yet to be conducted. Here, we examined a series of 4-substituted α-PHP analogs and found that, with one exception, all behaved as relatively (28to >300-fold) selective DAT versus serotonin transporter (SERT) reuptake inhibitors with DAT inhibition potencies of most falling within a very narrow (i.e., <3-fold) range. The 4-CF3 analog of α-PHP was a confirmed “outlier” in that it was at least 80-fold less potent than the other analogs and displayed reduced (i.e., no) DAT vs SERT selectivity. Consideration of various physicochemical properties of the CF3 group, relative to that of the other substituents involved here, provided relatively little insight. Unlike with DAT releasing agents, as previously reported by us, a QSAR study was precluded because of the limited range of empirical results (with the exception of the 4-CF3 analog) for DAT reuptake inhibition. Author Manuscript * Co-corresponding authors. , . Author Contributions: RAD performed the synthesis of the target compounds. Transporter studies were conducted by RAD and VTN under the supervision of JME. RAG proposed the project and prepared the initial draft of the manuscript; all co-authors had an opportunity to contribute to the final manuscript. Supporting Information (see separate file) Literature parameters/properties considered in ths investigation: Hammett σ and π substituent values, Verloop substituent length (L), Verloop maximal substituent width (B5), whole-molecule volume (Volume), and calculated Log P (cLogP) values. The authors claim no conflicting financial interests. Davies et al. Page 2 Author Manuscript Keywords Cathinone analogs; Dopamine transporter; DAT reuptake inhibition; Serotonin transporter; SERT reuptake inhibition; α-PVP; Drug abuse Introduction Author Manuscript α-Pyrrolidinohexiophenone (also referred to as α-pyrrolidinohexanophenone, α-PHP; 1) (Figure 1) is the one-carbon unit α-extended side-chain homolog of the better known and controlled (i.e., U.S. Schedule I) synthetic cathinone stimulant α-pyrrolidinovalerophenone (α-PVP). α-PVP (2, Figure 1), commonly known as “flakka” and by other “street” names, is the aryl ring-unsubstituted parent of another earlier controlled (i.e., U.S. Schedule I) substance, 3,4-methylenedioxypyrolovalerone (MDPV; 3) (Figure 1).1–3 Certain synthetic cathinones have been generically referred to as “bath salts”, of which MDPV (3) was, early on, sometimes a component; but, the term “bath salts” no longer refers to a specific or combination of agents. The term “bath salts” has radically evolved to include any of one or more synthetic cathinone analogs and even analogs of amphetamine/methamphetamine.1, 4 Author Manuscript Author Manuscript α-PHP (1) has been found on the clandestine market and now is also a controlled U.S. Schedule I substance.5 Various synthetic cathinones produce their central stimulant actions either by acting as substrates (i.e., as selective or non-selective monoamine neurotransmitter releasing agents), or as reuptake inhibitors (i.e., transport blockers), primarily at dopamine transporters (DAT) in the brain.1–4, 6–8 Synthetic cathinones can also act, depending upon their specific chemical structures (i.e., appended substituent groups), on norepinephrine and/or serotonin transporters (NET and SERT, respectively) (reviewed1, 4). That is, synthetic cathinones can influence synaptic monoamine neurotransmitter levels via one or more of several mechanisms (i.e., as substrates/releasing agents or as reuptake inhibitors/blockers of one or more monoamine transporters).4, 7, 8 Although many of these agents have yet to be examined in a comprehensive or systematic fashion, we have suggested on the basis of preliminary structure-activity evidence that synthetic cathinones seem to belong to two broad groups of agents: i) those possessing an extended α-alkyl side chain (i.e., longer/ larger than an α-methyl group) and/or a tertiary amine or bulky secondary terminal amine (i.e., complex synthetic cathinones), that typically behave as DAT reuptake inhibitors with reduced efficacy/potency at SERT, and ii) those with a primary amine or an N-methyl amine and either no α-, or an α-methyl, substituent (i.e., simple synthetic cathinones) that usually act as releasing agents at DAT but display little selectivity for DAT relative to SERT, depending upon pendant aryl substituents.3, 4, 9–11 These generalities are based on studies with a wide range of (often structurally-unrelated) agents or with relatively little direct systematic comparison. Furthermore, we have suggested that molecular determinants (i.e., various cathinone amine- and/or aryl-substituents) might differ for synthetic cathinonerelated agents acting as DAT reuptake inhibitors versus those acting as DAT releasing agents.11 Prior to the recent control of α-PHP (1) as a Scheduled substance, we examined 1 at DAT and found it to be at least as potent an inhibitor of DAT reuptake as its better known ACS Chem Neurosci. Author manuscript; available in PMC 2024 July 19. Davies et al. Page 3 Author Manuscript cousin α-PVP (2)12, consistent with more recent observations reported by others7, 8; α-PHP (1) was, coincidently, confiscated from the clandestine market at nearly the same time we reported the structure-activity relationships (SAR) of side-chain modified α-PVP analogs (that is, while our manuscript12 was in press). We showed that α-PHP possesses hallmarks of a new drug of abuse;12 and, this eventually was found to be the case.13–15 α- (...truncated)