title: Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release.
abstract: Synthetic cathinones are components of "bath salts" and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 "bath salt" components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (Kivalues) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinobutiophenone, α-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 4-methyl-α-pyrrolidinopropiophenone, α-pyrrolidinovalerophenone, 4-methoxy-α-pyrrolidinovalerophenone, α-pyrrolidinopentiothiophenone (alpha-PVT), and α-methylaminovalerophenone, and hDAT>hSERT>hNET for methylenedioxypentedrone. Increasing the α-carbon chain length increased the affinity and potency of the α-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT>hNET>hSERT except α-PPP and α-PVT, which had highest potencies at hNET. They did not induce [3H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloro-methcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-N-ethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [3H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus Ki/IC50ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone, and MDAI, which have higher potencies at hSERT than hDAT, may have empathogen psychoactivity.
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon eshleman@ohsu.edu.
authors: Amy J
authors: AJ
authors: Eshleman
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon.
authors: Katherine M
authors: KM
authors: Wolfrum
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon.
authors: John F
authors: JF
authors: Reed
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon.
authors: Sunyoung O
authors: SO
authors: Kim
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon.
authors: Tracy
authors: T
authors: Swanson
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon.
authors: Robert A
authors: RA
authors: Johnson
authors: Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon.
authors: Aaron
authors: A
authors: Janowsky
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism*; D050479:Neurotransmitter Transport Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D018377:Neurotransmitter Agents; D050479:Neurotransmitter Transport Proteins; C023665:cathinone