New analogues of ACPD with selective activity for group II metabotropic glutamate receptors.
In this study we have determined the pharmacology of a series of 1-aminocyclopentane-1,3-dicarboxylic acid (1,3-ACPD) analogues at cloned metabotropic glutamic acid (mGlu) receptors. The new analogues comprise the four possible stereoisomers of 1-amino-1-carboxycyclopentane-3-acetic acid (1,3-homo-ACPD) and the racemic mixture of (1RS,2RS)-1-amino-1-carboxycyclopentane-2-acetic acid (1RS,2RS-homo-ACPD), (1RS,2RS)-Homo-ACPD was shown to be a competitive mGlu2 receptor antagonist with a KB of 391 microM. (1S,3R)-Homo-ACPD and (1R,3R)-homo-ACPD were both shown to be mGlu2 receptor agonists with EC50 values of 122 and 105 microM, respectively. Compared to (S)-Glu both compounds displayed partial agonism with intrinsic activities of 79% and 47%, respectively. (1S,3S)-Homo-ACPD was also found to be a partial mGlu2 receptor agonist with an intrinsic activity of 27% compared to (S)-Glu. None of the compounds tested showed any activity at mGlu1a or mGlu4a receptors. These homo-ACPD's show a higher degree of subtype selectivity than the parent compound (1SR,3RS)-ACPD. In addition none of the compounds demonstrated any activity at ionotropic Glu receptors.
Bräuner-Osborne
H
H
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen Denmark. hans@medchem.dfh.dk
Madsen
U
U
Mikiciuk-Olasik
E
E
Curry
K
K
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D018698:Glutamic Acid