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Dr. John R. Atack "Pharmacological targets for Down syndrome"

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Published on Oct 29, 2011

The Search for Medicine for Down's Syndrome
Towards an International Research Alliance

September 17th 2011

The Wellcome Trust Conference Centre
Genome Campus
Hinxton, Cambridge, UK.


Program sponsored by
The Down's Syndrome Research Foundation UK
http://www.dsrf-uk.org
and a grant from Alzheimer's Research UK:
http://www.alzheimersresearchuk.org/


Dr. Atack is a Senior research Fellow in the department of Neuroscience Drug Discovery - at Johnson and Johnson's Janssen research facility in Beerse, Belgium. Having obtained his PhD in the Department of Pathology at Newcastle General Hospital, he then joined the National Institute on Aging near Washington DC where he was a postdoctoral fellow engaged in research into Alzheimer's Disease and Down syndrome. It was here that he gained his interest in pharmacology and upon his return to the UK joined the Merck Sharp and Dohme Neuroscience Research Centre in Harlow. He then moved to the Johnson and Johnson research site in La Jolla, California before relocating to Belgium. He is currently engaged in research to identify new drugs for the treatment of Alzheimer's Disease and schizophrenia.


Abstract:
FG7142 attenuates the inhibitory effects of GABA at GABAA receptors containing either an α1, α2, α3 or α5 subunit, and is therefore described as a non-selective inverse agonist. Although FG7142 enhances cognition in preclinical species, it is associated with profound anxiogenic effects in man. Recent advances in our understanding of which subtypes of GABAA receptor are associated with the various aspects of benzodiazepine pharmacology have defined the basis for developing subtype-selective GABAA modulators. More specifically, attenuation of the effects of GABA at the α5 subtype (i.e., benzodiazepine site inverse agonism) is associated with cognitive enhancement. Accordingly, a number of GABAA receptor subtype-selective compounds have been described, including the α5 selective inverse agonists α5IA, α5IA-II, MRK-016 and RO4938581. The purpose of the current presentation is to provide an update on α5IA and MRK-016, both of which progressed into man. Both compounds enhanced cognition in rats as measured using the delayed match-to-position version of the Morris water maze but importantly neither α5IA nor MRK-016 were proconvulsant or anxiogenic as assessed using the mouse pentylenetetrazole and rat elevated plus maze assays, respectively. Although α5IA progressed into man, preclinical renal toxicity studies meant α5IA was unsuitable for long-term dosing to a patient population. Nevertheless, in normal volunteers α5IA was not anxiogenic and was shown to reverse an ethanol-induced impairment in list recall in normal young volunteers. The back-up compound MRK-016 was well tolerated in young males but poorly tolerated in elderly subjects and this along with its variable human pharmacokinetics, precluded its further development. Collectively, these data clearly demonstrate that α5 subtype-selective GABAA compounds have pharmacological profiles in man that are distinct from non-selective GABAA modulators (i.e., FG7142) and although the clinical utility of such compounds remains to be unambiguously demonstrated should encourage the further pursuit of this molecular target.

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