The aim of this proposal is to discover the underlying basis for the devastating effect of new drugs entering the illicit market. What makes the project especially interesting is that these new drugs are structurally related to the well-known drugs, amphetamine and methamphetamine (AMPH and METH). One of the new drugs is cathinone (khat), a naturally occurring ?-keto derivative of AMPH~ another is methcathinone (MCAT), an analogous derivative of METH. The infamous and contemporary drug, bath salts, now penetrating our society with cruel effect, is composed of two additional derivatives of the basic ?-keto amphetamine structure, mephedrone (MEPH) and MDPV. To give a forerunner of a recent discovery, we believe that one of the bath salts ingredients (MEPH) is METH-like, i.e., a dopamine releaser via the human dopamine transporter (hDAT), while the other component (MDPV) is cocaine-like, acting as an hDAT blocker. This horrific combination may well account for the devastating effects reported by hospitals for bath salts victims. New drugs will continue t appear on the market, and it is difficult for the Food and Drug Administration to keep up with illegal variants and novel abuses. One of our objectives, therefore, is to codify structural varians of the ?-keto amphetamines (synthetic cathinones) that will predict their effects and speed societal and scientific responses to compounds as they appear on the street, and even before they appear. We approach this research from three complementary directions. First is our collaboration with a medicinal chemist, who will synthesize variations of the lead cathinones, to help understand important moieties and variations behind drug actions, and presently unavailable optical isomers to help uncover underlying mechanisms. Street drugs are invariably racemates, which we also study, but it is of interest to study right- and left-handed versions of synthetic cathinones to see which is more active and study possible positive or negative synergy between the two forms. Second, we will study the direct effect of street drugs and synthesized variants on the dopamine transporter in cell membranes under voltage and chemical control. How do METH and MCAT differ in their ability to stimulate transporters? Which of the synthetic cathinones are stimulants (producing electrical signals indicative of DA release) and which are blockers (producing inhibitory signals)? Because the drugs in question have overlapping effects on the dopaminergic and serotonergic systems, we will also study the biophysical effects of synthetic cathinones on the human serotonin transporter. Finally, we have teamed up with a neuropharmacologist who will measure the release of dopamine and serotonin in regions of the rodent brain associated with drug abuse and in response to specific synthetic cathinones or combination of drugs, as in bath salts. The abuse potential of test drugs will also be measured in self-administration protocols in rodents. We think this combined approach of medicinal chemistry, membrane biophysics, and neurochemistry and behavior has the potential to impact important problems in drug abuse to the benefit of basic science research and society in the 21st century.
Synthetic cathinones, also known colloquially as "Bath Salts," have been identified by the Drug Enforcement Agency as an emerging domestic drug abuse threat. This project will investigate molecular mechanisms and abuse-related pharmacology of cathinone and its synthetic derivatives using multidisciplinary tools of medicinal chemistry, membrane biophysics, and whole-animal neurochemistry and behavior. Results will clarify the threat and provide a basis for developing appropriate responses and treatments.
|Solis Jr, Ernesto; Suyama, Julie A; Lazenka, Matthew F et al. (2016) Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters. Sci Rep 6:31385|
|Hutsell, Blake A; Baumann, Michael H; Partilla, John S et al. (2016) Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats. Eur Neuropsychopharmacol 26:288-97|
|Suyama, Julie A; Sakloth, Farhana; Kolanos, Renata et al. (2016) Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin. J Pharmacol Exp Ther 356:182-90|
|De Felice, Louis J (2016) Chloride requirement for monoamine transporters. Pflugers Arch 468:503-11|
|Lazenka, Matthew F; Legakis, Luke P; Negus, S Stevens (2016) Opposing effects of dopamine D1- and D2-like agonists on intracranial self-stimulation in male rats. Exp Clin Psychopharmacol 24:193-205|
|Lazenka, Matthew F; Blough, Bruce E; Negus, S Stevens (2016) Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats. J Sex Med 13:338-49|
|Kolanos, R; Sakloth, F; Jain, A D et al. (2015) Structural Modification of the Designer Stimulant Î±-Pyrrolidinovalerophenone (Î±-PVP) Influences Potency at Dopamine Transporters. ACS Chem Neurosci 6:1726-31|
|Sakloth, F; Kolanos, R; Mosier, P D et al. (2015) Steric parameters, molecular modeling and hydropathic interaction analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172:2210-8|
|Gregg, Ryan A; Baumann, Michael H; Partilla, John S et al. (2015) Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats. Br J Pharmacol 172:883-94|
|Tang, Qiong-Yao; Kolanos, Renata; De Felice, Louis J et al. (2015) Structural analysis of dopamine- and amphetamine-induced depolarization currents in the human dopamine transporter. ACS Chem Neurosci 6:551-8|
Showing the most recent 10 out of 26 publications