Synthesis of novel allosteric agonists and allosteric modulators for nicotinic acetylcholine receptors

In healthy individuals, the α7 and α4β2 nAChRs are concentrated in regions of the brain involved with learning, cognition and memory, which are relevant to diseases such as Alzheimer’s disease. Hence, these receptors have become significant from a pharmacological and drug discovery perspective. The tetrahydroquinoline compound 4BP-TQS has been reported to act as a potent allosteric agonist on the α7 nAChR. The natural product desformylflustrabromine is able to act as a positive allosteric modulator (PAM) on the α4β2 nAChR. This thesis describes the development of synthetic routes directed towards 4BP-TQS and desformyflustrabromine analogues, and their pharmacological effects on α7 and α4β2 nAChRs. In the first half of the project a total of 51 analogues of 4BP-TQS were synthesized by performing a multicomponent reaction (MCR) between a substituted benzaldehyde, an aniline and an activated alkene. The pharmacological properties of these compounds were then studied by our collaborators in UCL pharmacology. These compounds exhibited interesting and wide ranging pharmacological properties with individual compounds acting as either allosteric agonists, antagonists, type I or type II positive allosteric modulators or allosteric antagonists of 4BP-TQS. The second part of the project involved the development of new chemistry directed towards the synthesis of desformylflustrabromine analogues. Initial work focused on the investigation of a novel Pd-catalysed allylation procedure for introducing an allyl group at the C-2 position of indole. Although the desired transformation was not successfully achieved, a novel regioselective Pd-catalysed C-3 diallylation of substituted indoles was discovered. The diallylated products were shown to be versatile intermediates which could undergo a variety of different reactions. By subjecting the diallylated products to ring-closing metathesis, a series of spirocyclic alkaloid-like structures were obtained in excellent yields. It was also demonstrated that the diallylated products could be desymmetrized using a proline-catalysed Mannich reactions to give enantioenriched products.