PHARMACOLOGY OF (S)-HOMOQUISQUALIC ACID AND (S)-2-AMINO-5-PHOSPHONOPENTANOIC ACID [(S)-AP5] AT CLONED METABOTROPIC GLUTAMATE RECEPTORS

1 In this study we have determined the pharmacological profile of (S)- quisqualic acid, (S)-2-amino-4-phosphonobutyric acid ((S)-AP4) and the ir higher homologues (S)-homoquisqualic acid, (S)-2-amino-5-phosphonop entanoic acid ((S)-AP5), respectively, and (R)-AP5 at subtypes of meta botropic (S)-glutamic acid (mGlu) receptors expressed in Chinese hamst er ovary cells. 2 (S)-Quisqualic acid was a potent mGlu(1)/mGlu(5) ago nist (EC50 values of 1.1 mu M and 0.055 mu M, respectively) showing no activity at mGlu(2) and weak agonism at mGlu(4) (EC(50)similar to 100 0 mu M). 3 (S)-Homoquisqualic acid displayed competitive antagonism at mGlu(1) (K-B=184 mu M) and full agonism at mGlu(5) (EC50=36 mu M) and mGlu(2) (EC50=23 mu M), but was inactive at mGlu(4). 4 (S)-AP4 was a potent and selective mGlu(4) agonist (EC50=0.91 mu M) being inactive a t mGlu(1), mGlu, and mGlu(5) both as agonist and antagonist. 5 (S)-AP5 displayed very weak agonist activity at mGlu(4). At the mGlu(2) recep tor subtype (S)-AP5 acted as a competitive antagonist (K-B=205 mu M), whereas the compound was inactive at mGlu(1) and mGlu(5). (R)-AP5 was inactive at all mGlu receptor subtypes tested both as agonist and anta gonist. 6 These studies demonstrate that incorporation of an additiona l carbon atom into the backbone of (S)glutamic acid and its analogues, to give the corresponding homologues, and replacement of the terminal carboxyl groups by isosteric acidic groups have profound effects on t he pharmacological profiles at mGlu receptor subtypes. Furthermore, (S )-homoquisqualic acid has been shown to be a potentially useful tool f or differentiating mGlu(1) and mGlu(5).