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| The UK Society for Intravenous Anaesthesia |
| Based in the UK - as a resource for Anaesthesia Worldwide |
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Annual Scientific Meeting, Belfast; November 2000. Designing New Drugs
Niall M. Hamilton and David K. Gemmell Organon Research, Newhouse Lanarkshire ML1 5SH There are a number of well-established and novel receptor targets for identifying new anaesthetics, analgesics and muscle relaxants. Selection of a target receptor has consequences for the methods that can be utilised to screen for drug leads e.g. assay throughput. Once a lead compound has been identified, synthetic modification is undertaken to improve its overall profile including pharmacokinetics and bioavailability. Owing to the limited structural information regarding binding sites of many receptors, drug discovery projects are still heavily reliant on ligand modification rather than rational design. Only when the interaction of a ligand with the active site of the target receptor is determined (via x-ray crystallography or NMR spectroscopy) can medicinal chemists precisely design improved drugs. Some typical problems that arise during the drug discovery process are discussed and illustrated using Org 25435, a GABAA receptor modulator that was developed as a potential new intravenous anaesthetic. This water-soluble compound was the culmination of a project aimed at improving upon propofol which, although an excellent anaesthetic, has a number of drawbacks associated with its use. Taking advantage of a lead compound identified from patent literature1 and employing a screening battery of in vitro and in vivo tests, the potency and anaesthetic profile of the lead compound was markedly improved (see Table). Table. Anaesthetic Activitya and GABAA Receptor Modulatory Effectsb of Org 25435
a Hypnotic dose 50 (HD50): the dose required to cause a loss of righting reflex for a minimum period of 30 s in 50 % of the treated mice upon intravenous administration over 10 s, sleep time (ST): measured at twice the HD50 dose and therapeutic index: (LD50/HD50) were determined using MF1 mice; b assessed via the ability to inhibit [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to rat whole brain membranes and electrophysiological results determined using oocytes expressing recombinant human a 1b 3g 2L GABAA receptors; c 95 % confidence limits; d morpholine; e bis(2-methoxyethyl)amine.The optimised derivative Org 25435 progressed through preclinical development and was evaluated in volunteers earlier this year. Although Org 25435 was an excellent anaesthetic using a single bolus administration, there were some side effects apparent when it was continuously infused that precluded further development. The presentation will conclude by assessing the market implications for designing new drugs within anaesthesiology. The good safety and reliability of current drugs, coupled with cost reduction pressures and the prospect of current agents becoming generic, means there is limited opportunity to improve on current anaesthetics and muscle relaxants. Drug discovery projects are therefore more likely to focus on identifying new analgesics, where there is a greater unmet clinical need and more opportunity to improve on existing agents such as the opiates. 1 (a) D. G. Bamford, D. F. Biggs, G. E. Lee, A. J. Owen, D. W. Pulsford and W. R. Wragg, British Patent Specification 1,160,468; (b) A. H. Loveless and D. R. Maxwell, The prevention by sulphydryl compounds of the toxicity in the cat of 2,6-dimethoxyphenol and its morpholinopropionyl ester. Br. J. Pharmacol. 1975, 53, 93-98. |
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