Medicinal Chemistry of Drugs Acting on Biogenic Amine Receptors

National Institute On Drug Abuse

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Abstract

Designer drug abuse has continued unabated in the U.S., Europe and elsewhere during the reporting period. These designer drugs are a diverse and rapidly changing group of synthetic materials that are designed to mimic the effects of controlled drugs. Recently, the most commonly encountered substances are designer cannabinoids and psychomotor stimulants. The latter, the so-called bath salts (e.g. MDPV and alpha-PVP aka flakka,) are powerful and extremely dangerous psychomotor stimulants that represent a highly significant threat to public health worldwide. A major problem with these substances is that the user is generally unaware of the identity or even the effects of these preparations. Many such preparations have been seized by the authorities and most often contain synthetic derivatives of cathinone. Mephedrone and methylone are among the most commonly identified bath salts in recent US seizures. Some of these drugs produce very bizarre, unpredictable, and irrational human behavioral effects. There are major problems in preventing the abuse of these drugs. First, these compounds are relatively simple and cheap to produce from chemicals readily available worldwide. Second, once the U.S. Drug Enforcement Administration (DEA) uses its emergency scheduling authority to place one generation of cathinones (MDPV, mephedrone, and methylone) under Schedule I (the most stringent) regulations, the next generation of structurally and pharmacologically similar designer drugs quickly emerge on the market as the traffickers attempt to introduce new and unregulated replacements. In addition, a large proportion of these substances are produced by Asian criminal groups and are sent through the U.S. mail in innumerable small packages greatly complicating interdiction efforts of the DEA and other law enforcement groups. This is not only a U.S. problem as nearly identical situations exist in Europe and elsewhere. The continuous appearance of new designer drugs requires a rapid and definitive assessment of the danger presented by each individual substance. Such studies in animals require substantial quantities of the pure, authentic drug substance in order to enable the appropriate studies in a timely manner. In order to gain further insight into the cathinones as a drug class, we synthesized and studied the pharmacologic properties and abuse potential of an array of cathinones including first- (MDPV) and select second-generation (MDPBP, MDPPP, alpha-PVP, and alpha-PPP) synthetic cathinones and aimed to identify any structural determinants of their actions at monoamine transporters as well as their reinforcing potency and/or effectiveness. We first studied racemic MDPV and alpha-PVP in a progressive ratio self-administration paradigm in rhesus monkeys. The most potent reinforcer was MDPV, followed by -PVP, methamphetamine, and cocaine in that order. Alpha-PVP was the most effective reinforcer, followed by MDPV, cocaine, and methamphetamine. In addition to making more responses to obtain MDPV and alpha-PVP, monkeys also responded for longer periods of time when MDPV or Alpha-PVP was available compared with when either cocaine or methamphetamine was available for infusion. Our present studies confirm recent reports in rodents that the synthetic cathinones MDPV and -PVP are capable of maintaining high levels of responding for prolonged periods of time and that they function as more effective reinforcers than either cocaine or methamphetamine. Our results may account for the high rates of bath salts use reported in humans.