NEW ANALOGS OF ACPD WITH SELECTIVE ACTIVITY FOR GROUP-II METABOTROPICGLUTAMATE RECEPTORS

In this study we have determined the pharmacology of a series of 1-ami nocyclopentane-1,3-dicarboxylic acid(1,3-ACPD) analogues at cloned met abotropic glutamic acid (mGlu) receptors. The new analogues comprise t he four possible stereoisomers of 1-amino-1-carboxycyclopentane-3-acet ic acid (1,3-homo-ACPD) and the racemic mixture of (1 RS,2RS)-1-amino- 1-carboxycyclopentane-2-acetic (1 RS,2RS-homo-ACPD). (1RS,2RS)-Homo-AC PD was shown to be a competitive mGlu(2) receptor antagonist with a K- B, of 391 mu M (1S,3R)-Homo-ACPD and (1R,3R)-homo-ACPD were both shown to be mGlu(2) receptor agonists with EC50 values of 122 and 105 mu M, respectively. Compared to (S)-Glu both compounds displayed partial ag onism with intrinsic activities of 79% and 47%, respectively. (1S,3S)- Homo-ACPD was also found to be a partial mGlu(2) receptor agonist with an intrinsic activity of 27% compared to (S)-Glu. None of the compoun ds tested showed any activity at mGlu(1 alpha) or mGlu(4a) 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 dem onstrated any activity at ionotropic Glu receptors. (C) 1997 Elsevier Science B.V.