MOLECULAR PHARMACOLOGY OF HOMOLOGS OF IBOTENIC ACID AT CLONED METABOTROPIC GLUTAMIC-ACID RECEPTORS

We have studied the effects of the enantiomers of 2-amino-3-(3-hydroxy isoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) and analogues s ubstituted with a methyl, bromo or butyl group in the four position of the ring at cloned metabotropic glutamate (mGlu) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast to the parent compou nd ibotenic acid, which is a potent group I and II agonist, the (S)-fo rms of homoibotenic acid and its analogues are selective and potent gr oup I antagonists whereas the (R)-forms are inactive both as agonists and antagonists at group I, II, and III mGlu receptors. Interestingly, (S)-homoibotenic acid and the analogues display equal potency at both mGlu(1 alpha) and mGlu(5a) with K-i values in the range of 97 to 490 mu M, (S)-homoibotenic acid and (S)-2-amino-3-(4-butyl-3-hydroxyisoxaz ol acid [(S)-4-butylhomoibotenic acid] displaying the lowest and highe st potency, respectively. The homoibotenic acid analogues thereby diff er from mGlu receptor antagonists derived from phenylglycine such as ( S)-4-carboxyphenylglycine which only antagonizes mGlu(1 alpha) (K-i = 18 mu M) showing no effect at mGlu(5a) (K-i > 300 mu M). (C) 1998 Else vier Science B.V. All rights reserved.