Pharmacology of (S)‐homoquisqualic acid and (S)‐2‐amino‐5‐phosphonopentanoic acid [(S)‐AP5] at cloned metabotropic glutamate receptors

In this study we have determined the pharmacological profile of ( S )‐quisqualic acid, ( S )‐2‐amino‐4‐phosphonobutyric acid (( S )‐AP4) and their higher homologues ( S )‐homoquisqualic acid, ( S )‐2‐amino‐5‐phosphonopentanoic acid (( S )‐AP5), respectively, and ( R )‐AP5 at subtypes of metabotropic ( S )‐glutamic acid (mGlu) receptors expressed in Chinese hamster ovary cells. ( S )‐Quisqualic acid was a potent mGlu 1 /mGlu 5 agonist (EC 50 values of 1.1 μ M and 0.055 μ M , respectively) showing no activity at mGlu 2 and weak agonism at mGlu 4 (EC 50 ∼1000 μ M ). ( S )‐Homoquisqualic acid displayed competitive antagonism at mGlu 1 ( K B =184 μ M ) and full agonism at mGlu 5 (EC 50 =36 μ M ) and mGlu 2 (EC 50 =23 μ M ), but was inactive at mGlu 4 . ( S )‐AP4 was a potent and selective mGlu 4 agonist (EC 50 =0.91 μ M ) being inactive at mGlu 1 , mGlu 2 and mGlu 5 both as agonist and antagonist. ( S )‐AP5 displayed very weak agonist activity at mGlu 4 . At the mGlu 2 receptor subtype ( S )‐AP5 acted as a competitive antagonist ( K B =205 μ 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 antagonist. These studies demonstrate that incorporation of an additional 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 the pharmacological profiles at mGlu receptor subtypes. Furthermore, ( S )‐homoquisqualic acid has been shown to be a potentially useful tool for differentiating mGlu 1 and mGlu 5 .British Journal of Pharmacology (1998) 123 , 269–274; doi: 10.1038/sj.bjp.0701616