Abuse-related and neurocognitive consequences of halogenated arylcyclohexylamines.

About This Grant

PROJECT SUMMARY This application focuses on synthetic psychoactive drugs (SPDs), specifically novel arylcyclohexylamine (ACX) analogues of phencyclidine (PCP) and ketamine. Recently, novel ACXs have appeared on the illicit market, driven by their relative ease of synthesis and the chemical scaffold's versatility, allowing clandestine chemists to tailor the pharmacological profile of each analog. For example, the parent drugs PCP and ketamine are primarily non-competitive NMDA antagonists while the analogue bromadol is an extremely potent μ-opioid agonist. Structural modifications thus yield radically distinct pharmacological actions, and mechanisms can not necessarily be assumed based solely on chemical structure. Ring halogenation is a common structural modification among other classes of SPDs. Successive generations of designer amphetamines, opioids, synthetic cannabinoid receptor agonists, and “bath salts” cathinones are all characterized by halogen group substitutions, and novel halogenated analogues of PCP and ketamine are currently emerging as drugs of abuse. This proposal takes a proactive approach to study these emerging ACXs and to anticipate novel halogenated ACX drugs of concern in order to develop preclinical profiles of these compounds regarding their abuse-related and neurocognitive effects. Our goal is to synthesize new halogenated “classical” PCP-like ACXs and more structurally complex ACX drugs with opioid-like actions, then characterize their behavioral pharmacology using rodent models of drug discrimination, intravenous self-administration, and neurocognitive impairment perhaps relevant to PCP-elicited psychosis. The rationale for the proposed research is that the relative danger of these substances to public health is unknown, and more information on how modifications to the ACX base structure affect pharmacological action is needed. Our central hypothesis is that abuse-related effects will correlate with neurocognitive disruption among ring-halogenated ACXs with classical PCP-like effects, but not among more elaborated ACXs with opioid actions. In Aim 1, we will synthesize a library of ring-halogenated “classical” PCP- like ACXs and a series of more elaborate opioid-like ACXs. In Aim 2, we will determine their interactions with NMDA and opioid receptors in vitro along with their metabolic disposition in vivo, and further screen these drugs for off-target binding. Finally, in Aim 3, abuse-related and neurocognitive effects of novel ACXs in male and female rats will be tested using assays of drug discrimination, intravenous self-administration, pre-pulse inhibition of the acoustic startle response, and an operant assay of rule-governed behavior modeling attentional set- shifting. Our proposed studies will be the first to provide behavioral characterization of these novel drugs, which will be essential for understanding the dangers these emerging drugs pose to the public health.