Restriction lift date: 2032-10-31
Studies in the synthesis and analysis of novel heterocyclic synthetic cannabinoid receptor agonists
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Date
2022-03-08
Authors
Alam, Ryan
Journal Title
Journal ISSN
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Publisher
University College Cork
Published Version
Abstract
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.
Description
Keywords
N-alkylation , Aminocarbonylation , Azaindazole , Indazole , New psychoactive substance , Structure-activity relationship , Regioselective , Synthetic cannabinoid receptor agonist
Citation
Alam, R. M. 2022. Studies in the synthesis and analysis of novel heterocyclic synthetic cannabinoid receptor agonists. PhD Thesis, University College Cork.