brain sciences Review U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market Michael H. Baumann 1,*, Graziella Tocco 2 , Donna M. Papsun 3, Amanda L. Mohr 4, Melissa F. Fogarty 4 and Alex J. Krotulski 4 1 Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD 21224, USA 2 Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy; [email protected] 3 Toxicology Department, NMS Labs, 200 Welsh Road, Horsham, PA 19044, USA; [email protected] 4 Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, 2300 Stratford Ave, Willow Grove, 19090 PA, USA; [email protected] (A.L.M.); [email protected] (M.F.F.); [email protected] (A.J.K.) * Correspondence: [email protected] Received: 23 October 2020; Accepted: 18 November 2020; Published: 23 November 2020 Abstract: The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent µ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs. Keywords: analytical chemistry; forensic toxicology; mu-opioid receptor; opioid pharmacology; U-compounds 1. Introduction The misuse of opioid drugs is a serious public health concern [1]. In particular, a dramatic rise in opioid-induced intoxications and fatalities is being driven by illicitly manufactured fentanyl appearing in non-medical (i.e., recreational) drug markets worldwide [2,3]. An additional disturbing trend is the emergence of novel synthetic opioids (NSOs) that are encountered as standalone products, adulterants in illicit heroin, or constituents of counterfeit pain medications [4–6]. Here, we define NSOs to include fentanyl analogs and non-fentanyl-related compounds that function as potent and efficacious µ-opioid receptor (MOR) agonists. NSOs present complex challenges for public health and safety since these drugs are often more potent than heroin or morphine, and they are not detected by standard toxicology Brain Sci. 2020, 10, 895; doi:10.3390/brainsci10110895 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 895 2 of 30 Brain Sci. 2020, 10, x FOR PEER REVIEW 2 of 31 drug testing methods [7,8]. Most NSOs are not “new” chemical entities, rather, they are resurrected by standard toxicology drug testing methods [7,8]. Most NSOs are not “new” chemical entities, from older patent and medicinal chemistry literature where their potency and efficacy are often reported. rather, they are resurrected from older patent and medicinal chemistry literature where their potency Since the 1970s, pharmaceutical companies and medical researchers have sought to discover and and efficacy are often reported. Since the 1970s, pharmaceutical companies and medical researchers develop new analgesic agents with reduced propensity for undesirable side-effects, such as tolerance, have sought to discover and develop new analgesic agents with reduced propensity for undesirable dependence, and respiratory depression. Some of these potential medications, belonging to different side-effects, such as tolerance, dependence, and respiratory depression. Some of these potential chemical classes, have been diverted as NSOs to the recreational drug supply [9,10]. In this regard, medications, belonging to different chemical classes, have been diverted as NSOs to the recreational phenampromide [11], MT-45 [12,13], AH-7921 [14,15], U-47700 [16,17], and U-50488 [18,19] are notable drug supply [9,10]. In this regard, phenampromide [11], MT-45 [12,13], AH-7921 [14,15], U-47700 examples of structurally distinct analgesic compounds that never advanced to human clinical trials [16,17], and U-50488 [18,19] are notable examples of structurally distinct analgesic compounds that (see Figure1 for chemical structures). U-47700 and U-50488 are part of an N-substituted benzamide never advanced to human clinical trials (see Figure 1 for chemical structures). U-47700 and U-50488 andare 2-phenylacetamidepart of an N-substituted seriesof benzamide compounds and that 2-phenylacet was exploredamide by the series Upjohn of compounds Company in that the 1970swas andexplored 1980s by as potentialthe Upjohn therapeutic Company agents. in the 1970s Drugs and in these 1980s series as potential can be referredtherapeutic to as agents. “U-compounds” Drugs in (orthese “U-series” series can compounds, be referred or informallyto as “U-compounds as “Utopioids”),” (or with“U-series” the “U” compounds, attributable or to informally their company as of“Utopioids”), origin. with the “U” attributable to their company of origin. N O O N N N Cl N N H Cl MT-45 PHENAMPROMIDE AH-7921 Cl O O Cl N N Cl N N Cl U-47700 U-50488H FigureFigure 1.1. ChemicalChemical structures structures of of novel novel synthetic synthetic opioids opioids (NSOs) (NSOs) containing containing 1,2-ethylene 1,2-ethylene diamine diamine core corecomponents. components. ItIt is is hypothesized hypothesized thatthat U-compoundsU-compounds emergedemerged as NSOs due to to their their desirable desirable opioid-mediated opioid-mediated eeffectsffects (i.e., (i.e., euphoriaeuphoria andand painpain relief),relief), togethertogether withwith ease of synthesis and and availability availability of of precursor precursor chemicalschemicals or or starting starting materialsmaterials [[20,21].20,21]. Clandestine drug products products containing containing U-47700 U-47700 are are nicknamed nicknamed “pink”,“pink”, “U4”, “U4”, or or “pink “pink heroin” heroin” byby drugdrug distributorsdistributors and consumers, and and more more recently recently this this drug drug was was identifiedidentified asas a a constituent constituent inin thethe potentpotent opioidopioid cocktailcocktail “gray death” [22]. [22]. Studies Studies using using laboratory laboratory animalsanimals showshow thatthat U-47700U-47700 isis aboutabout 10-times more potent than than morphine morphine as as an an analgesic analgesic agent agent [23], [23], andand this this enhanced enhanced potencypotency couldcould bebe responsibleresponsible for the intoxications and and mortality mortality associated associated with with thethe compound compound [ [24–27].24–27]. PublishedPublished reviews about U-47 U-47700700 have have covered covered its its history history and and diversion diversion [20], [20], syntheticsynthetic schemesschemes andand structurestructure activityactivity relationshipsrelationships (SAR) (SAR) [21], [21], as as well well as as clinical clinical symptoms symptoms [28]. [28 ]. Here,Here, we we provide provide an updatedan updated review review of the of medicinal the medicinal chemistry, chemistry, preclinical preclinical pharmacology, pharmacology, clandestine availability,clandestine methods availability, for detection, methods and for forensicdetection, toxicology and forensic of U-47700 toxicology and selected of U-47700 analogs. and A completeselected summaryanalogs. A of complete the human summary casework of involvingthe human U-47700 casework intoxication involving andU-47700 death intoxication is included. and death is included. 2. Medicinal Chemistry 2. MedicinalAll of the Chemistry NSOs depicted in Figure1 are non-fentanyl-related compounds that share a strategicAll of 1,2-ethylene the NSOs depicted diamine in core Figure sca ff1 oldare non-fentanyl-related with vast potential compounds for side chain that substitutions share a strategic and rearrangements,1,2-ethylene diamine thereby core serving scaffold as a template with vast for a varietypotential of structurallyfor side chain related substitutions analogs [29]. Withand rearrangements, thereby serving as a template for a variety of structurally related analogs [29]. With Brain Sci. 2020, 10, 895x FOR PEER REVIEW 3 of 31 30 the exception of MT-45, all of these compounds possess two nitrogen atoms with very different chemicalthe exception and ofelectrochemical MT-45, all of characteristics, these compounds so they possess can twobe better nitrogen defined atoms as with N-(2-ethylamino) very different chemical and electrochemical characteristics, so they can be better defined as N-(2-ethylamino) amides. amides. More specifically, these compounds possess one sp3 hybridized