'Acts of Extravagance and Folly’: the conception and control of transgressive masculinity in a Victorian cause célèbre

Based on the prosecution of Ernest Boulton and William Park in 1870, the cross-dressing cause célèbre of the Victorian period, this Thesis explores the complex interplay of gendered nineteenth century narratives that emerged in both public and institutional discourse as a result of the arrest and prosecution for conspiracy to commit sodomy of the male cross-dressers and their acquaintances. Within the current historiography of the nineteenth century the regulation of male cross-dressers has been associated with the reflexive homophobia that has come to dominate modern interpretations of Victorian conceptions of male gender deviance. Whilst accepting that the case of Boulton and Park has rightly found its place within the established narrative histories of male sexuality this Thesis argues that the case, and indeed the image of the male cross-dresser in general, illuminates much more than nascent Victorian conceptions of homosexuality. The effeminacy of the cross-dresser, although universally stigmatised, is shown to represent a multitude of social ills ranging from economic indolence to moral degeneracy, placing the cross-dresser at the nexus of bourgeoisie social anxiety. Through the detailed analysis of legal transcripts and press reports this Thesis demonstrates the significance of the analysis of the male cross-dresser beyond the narrow confines of the history of sexuality. The prosecution of Boulton and Park attests to more than the increasingly reactionary policing of bourgeois conceptions of masculinity during the mid to late nineteenth century. The unprecedented publicity that accompanied the case combined with the cross-dresser’s ability to unite previously disparate strands of deviant discourses, like those of the female prostitute and male sodomite, will be shown to represent a rare moment in which the totality of bourgeois anxiety was manifest, a moment in which the cross-dresser became the gendered folk devil for an age of ideological temperance

Synthesis and Pharmacological Profiling of the Metabolites of Synthetic Cannabinoid Drugs APICA, STS-135, ADB-PINACA, and 5F-ADB-PINACA

Synthetic cannabinoids (SCs) containing a 1-pentyl-1-<i>H</i> substituted indole or indazole are abused around the world and are associated with an array of serious side effects. These compounds undergo extensive phase 1 metabolism after ingestion with little understanding whether these metabolites are contributing to the cannabimimetic activity of the drugs. This work presents the synthesis and pharmacological characterization of the major metabolites of two high concern SCs; APICA and ADB-PINACA. In a fluorometric assay of membrane potential, all metabolites that did not contain a carboxylic acid functionality retained potent activity at both the CB₁ (EC₅₀ = 14–787 nM) and CB₂ (EC₅₀ = 5.5–291 nM) receptors regardless of heterocyclic core or 3-carboxamide substituent. Of note were the 5-hydroxypentyl and 4-pentanone metabolites which showed significant increases in CB₂ functional selectivity. These results suggest that the metabolites of SCs potentially contribute to the overall pharmacological profile of these drugs

Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues

Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB₁ (EC₅₀ = 0.43–12.3 nM) and CB₂ (EC₅₀ = 11.3–122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB₁ activation (3.1–53 times over CB₂). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB₁, but not CB₂, antagonist, confirming that cumyl-derived SCs are cannabimimetic in vivo

Pharmacology of Valinate and <i>tert</i>-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-<i>tert</i>-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB₁ (EC₅₀ = 0.45–36 nM) and CB₂ (EC₅₀ = 4.6–128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB₁ activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1–1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 °C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB₁, but not CB₂, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB₁-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Δ⁹-THC and earlier generations of SCs

Development of Bright and Biocompatible Nanoruby and Its Application to Background-Free Time-Gated Imaging of G‑Protein-Coupled Receptors

At the forefront of developing fluorescent probes for biological imaging applications are enhancements aimed at increasing their brightness, contrast, and photostability, especially toward demanding applications of single-molecule detection. In comparison with existing probes, nanorubies exhibit unlimited photostability and a long emission lifetime (∼4 ms), which enable continuous imaging at single-particle sensitivity in highly scattering and fluorescent biological specimens. However, their wide application as fluorescence probes has so far been hindered by the absence of facile methods for scaled-up high-volume production and molecularly specific targeting. The present work encompasses the large-scale production of colloidally stable nanoruby particles, the demonstration of their biofunctionality and negligible cytotoxicity, as well as the validation of its use for targeted biomolecular imaging. In addition, optical characteristics of nanorubies are found to be comparable or superior to those of state-of-the-art quantum dots. Protocols of reproducible and robust coupling of functional proteins to the nanoruby surface are also presented. As an example, NeutrAvidin-coupled nanoruby show excellent affinity and specificity to μ-opioid receptors in fixed and live cells, allowing wide-field imaging of G-protein coupled receptors with single-particle sensitivity

The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse

Two novel adamantane derivatives, adamantan-1-yl­(1-pentyl-1<i>H</i>-indol-3-yl)­methanone (AB-001) and <i>N</i>-(adamtan-1-yl)-1-pentyl-1<i>H</i>-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure–activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB₁ (EC₅₀ = 16–43 nM) and CB₂ (EC₅₀ = 29–216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB₂ receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ⁹-tetrahydrocannabinol (Δ⁹-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Δ⁹-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ⁹-THC, JWH-018, and SDB-001

Data_Sheet_1_Synthesis and pharmacological evaluation of newly detected synthetic cannabinoid receptor agonists AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA, MDMB-4F-BUTINACA and their analogs.docx

Synthetic cannabinoid receptor agonists (SCRAs) continue to make up a significant portion new psychoactive substances (NPS) detected and seized worldwide. Due to their often potent activation of central cannabinoid receptors in vivo, use of SCRAs can result in severe intoxication, in addition to other adverse health effects. Recent detections of AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA and MDMB-4F-BUTINACA mark a continuation in the appearance of SCRAs bearing novel tail substituents. The proactive characterization campaign described here has facilitated the detection of several new SCRAs in toxicological case work. Here we detail the synthesis, characterization, and pharmacological evaluation of recently detected SCRAs, as well as a systematic library of 32 compounds bearing head, tail, and core group combinations likely to appear in future. In vitro radioligand binding assays revealed most compounds showed moderate to high affinity at both CB1 (pKi = 2 (pKi = 5.49 ± 0.03 to 9.92 ± 0.09 M) receptors. In vitro functional evaluation using a fluorescence-based membrane potential assay showed that most compounds were sub-micromolar to sub-nanomolar agonists at CB1 (pEC50 = 2 (pEC50 = 5.92 ± 0.16 to 8.64 ± 0.15 M) receptors. An in silico receptor-ligand docking approach was utilized to rationalize binding trends for CB2 with respect to the tail substituent, and indicated that rigidity in this region (i.e., 4-cyanobutyl) was detrimental to affinity.</p