William Jorgensen (PhD 2018) is an emerging leader in drug discovery and research translation. He has previously received the NHMRC Peter Doherty Biomedical Fellow (2019-2021) and has led numerous programs resulting in commercial outcomes. His PhD focused on the development of CNS penetrant oxytocin receptor agonists culminating in 5 patent applications (4 granted) which resulted in the formation of Kinoxis Therapeutics which has successfully completed a phase 1 clinical trial. His post-doctoral work involved the optimisation of a brain penetrant tubulin inhibitor for the treatment of glioblastoma. This work resulted in the two patent applications and is the key asset in pre-seed fundraising negotiations at the University of Sydney for the inception of a spin-off company. For the past 3 years he has overseen the drug discovery and optimisation efforts at Xylo.bio as the director of medicinal chemistry.

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The development of serotonergic 2A receptor agonists inspired by psychedelic natural products.

Psylo has used a combination of high-throughput virtual screening and rational drug design to develop a library of 5-HT2A agonists with antidepressant-like activity in rodent models. This presentation will describe our unique approach to the identification of new chemical matter with 5-HT2A activity, as well as lead optimization efforts. Details of the medicinal chemistry, 5-HT (and off-target) receptor profiling, in vitro neuroplasticity, in vivo pharmacokinetics, and behavioural pharmacology of this therapeutic class will be described.

Pharmacological and pharmacokinetic characterization of 6-F-DET:
6-Fluoro-N,N-diethyltryptamine (6-F-DET) is an historical tryptamine that was used as an active control in the clinical study of numerous psychedelics in the 1970s. 6-F-DET shares structural similarities and common pharmacological targets to many psychedelic tryptamines, however, it fails to elicit a characteristic profile in the head twitch response assay. In recent years, 6-F-DET has been used as a “non-hallucinogenic” pharmacological tool to elucidate psychedelic mechanisms, despite descriptions of non-psychedelic or atypical psychoactivity in early clinical work. We have comprehensively profiled the receptor interactions of 6-F-DET at more than 40 5-HT and non-5HT targets within the central nervous system, as well as detailing the pharmacokinetic properties of 6-F-DET in mice. We have confirmed the HTR profile of 6-F-DET and correlated brain exposure levels to effective receptor concentrations at multiple targets  and explored the interaction of 6-F-DET with classical and novel psychedelics in mice. An overview of the historical exploration of 6-F-DET will be presented, as well as our recent pharmacological and pharmacokinetic profiling, and preliminary “behavioral fingerprinting” via a proprietary machine learning classifier.