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Conversion of the Mushroom Toxin Muscimol into THIP (Gaboxadol), a Novel Type of Hypnotic and Non-Opioid Analgesic
Povl Krogsgaard-Larsen
Denmark

Muscimol is a toxic heterocyclic 3-isoxazolol bioisostere of GABA, showing high affinity for the GABA_A receptors. The corresponding α-aminocarboxylic acid, ibotenic acid, is a powerful glutamate receptor agonist and has been extensively used as a lead structure. THIP is a specific GABA_A agonist, whereas THPO is a specific GABA uptake inhibitor. THIP actually is a partial GABA_A agonist at GABA_A receptors with different subunit combinations. The isosteric amino acids isonipecotic acid and nipecotic acid were shown to possess potent and highly selective GABA_A agonist and GABA uptake inhibitor effects.





The zwitterionic structures of muscimol, THIP, and THPO do not prevent these compounds from entering the brain after systemic administration. THIP is well tolerated in man. THIP (under the name Gaboxadol) is an agent showing potent non-opioid analgesic effects and an ability to re-establish normal sleep architecture in patients with disturbed sleep patterns. Gaboxadol is now in clinical trials in depression.