TY - JOUR
T1 - Pharmacology of (S)-homoquisqualic acid and (S)-2-amino-5-phosphonopentanoic acid [(S)-AP5] at cloned metabotropic glutamate receptors
AU - Bräuner-Osborne, Hans
AU - Krogsgaard-Larsen, P
PY - 1998/1
Y1 - 1998/1
N2 - 1 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. 2 (S)-Quisqualic acid was a potent mGlu1/mGlu5 agonist (EC50 values of 1.1 microM and 0.055 microM, respectively) showing no activity at mGlu2 and weak agonism at mGlu4 (EC50 approximately 1000 microM). 3 (S)-Homoquisqualic acid displayed competitive antagonism at mGlu1 (KB = 184 microM) and full agonism at mGlu5 (EC50 = 36 microM) and mGlu2 (EC50 = 23 microM), but was inactive at mGlu4. 4 (S)-AP4 was a potent and selective mGlu4 agonist (EC50 = 0.91 microM) being inactive at mGlu1, mGlu2 and mGlu5 both as agonist and antagonist. 5 (S)-AP5 displayed very weak agonist activity at mGlu4. At the mGlu2 receptor subtype (S)-AP5 acted as a competitive antagonist (KB = 205 microM), whereas the compound was inactive at mGlu, and mGlu5. (R)-AP5 was inactive at all mGlu receptor subtypes tested both as agonist and antagonist. 6 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 mGlu1 and mGlu5.
AB - 1 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. 2 (S)-Quisqualic acid was a potent mGlu1/mGlu5 agonist (EC50 values of 1.1 microM and 0.055 microM, respectively) showing no activity at mGlu2 and weak agonism at mGlu4 (EC50 approximately 1000 microM). 3 (S)-Homoquisqualic acid displayed competitive antagonism at mGlu1 (KB = 184 microM) and full agonism at mGlu5 (EC50 = 36 microM) and mGlu2 (EC50 = 23 microM), but was inactive at mGlu4. 4 (S)-AP4 was a potent and selective mGlu4 agonist (EC50 = 0.91 microM) being inactive at mGlu1, mGlu2 and mGlu5 both as agonist and antagonist. 5 (S)-AP5 displayed very weak agonist activity at mGlu4. At the mGlu2 receptor subtype (S)-AP5 acted as a competitive antagonist (KB = 205 microM), whereas the compound was inactive at mGlu, and mGlu5. (R)-AP5 was inactive at all mGlu receptor subtypes tested both as agonist and antagonist. 6 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 mGlu1 and mGlu5.
KW - 2-Amino-5-phosphonovalerate
KW - Animals
KW - CHO Cells
KW - Cloning, Molecular
KW - Cricetinae
KW - Excitatory Amino Acid Antagonists
KW - Quisqualic Acid
KW - Receptors, Metabotropic Glutamate
KW - Stereoisomerism
U2 - 10.1038/sj.bjp.0701616
DO - 10.1038/sj.bjp.0701616
M3 - Journal article
C2 - 9489615
SN - 0007-1188
VL - 123
SP - 269
EP - 274
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 2
ER -