Studies in the synthesis and analysis of novel heterocyclic synthetic cannabinoid receptor agonists

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Alam, Ryan
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University College Cork
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Over the past decade, synthetic cannabinoid receptor agonists (SCRA) have come to represent a diverse category of new psychoactive substance (NPS). However, from a chemical perspective, little is known about the clandestine chemical syntheses of SCRAs. To contextualise the latter paucity of information, this thesis introduces the pharmacological significance of the endocannabinoid system and describes the subsequent advances that have been made to develop synthetic cannabinoid-based therapeutics. The repurposing of cannabinoids that were developed as a part of legitimate drug discovery programmes, for recreational use as illicit NPS, is then discussed with a particular focus on the structural diversity, toxicological adverse effects, legislative control, and chemical characterisation of newly emerging SCRA ligands. Following the assembly of the key heterocyclic building block in the synthesis of indazole-type SCRA ligands, 1H-indazole-3-carboxylic acid, this work describes the development and application of a protocol for the regioselective (>99%) N-1 alkylation of the indazole scaffold to generate a wide range of structurally diverse N-1 substituted indazole derivatives in excellent yield (up to 99%). Additionally, the latter optimised N-alkylation protocol is also shown to regioselectively (> 99%) afford N-2 substituted indazoles. Through the variation of “tail” and “head” group motifs inspired by structural trends observed in newly emerging cannabimimetic SCRA NPS, we have generated a prophetic library of novel 1,3-disubstituted indazole-3-carboxamide derivatives. The subsequent discussion of notable spectroscopic features of these heterocyclic SCRA analogues provides further information of forensic interest. Finally, the development and optimisation of a methodology for an expedient approach to analogous, novel, 1,3-disubstituted pyrazolo[3,4-b]pyridine-3- carboxamide SCRA derivatives in high yield (up to 99%), via palladium-catalysed aminocarbonylation is described. This aminocarbonylation protocol is applied to the synthesis of isomeric 4-, 5-, 6-, and 7-azaindazole analogues of the known illicit indazole SCRA ligand, MDMB-PINACA, to facilitate their unambiguous spectroscopic differentiation and structural confirmation. The latter work provides a robust and convenient methodology for the synthesis of pyrazolopyridine-3-carboxamides and presents the first reported spectroscopic discussion of azaindazole-type SCRA NPS.
N-alkylation , Aminocarbonylation , Azaindazole , Indazole , New psychoactive substance , Structure-activity relationship , Regioselective , Synthetic cannabinoid receptor agonist
Alam, R. M. 2022. Studies in the synthesis and analysis of novel heterocyclic synthetic cannabinoid receptor agonists. PhD Thesis, University College Cork.