SYNTHESIS AND BIOLOGY OF THE CONFORMATIONALLY RESTRICTED ACPD ANALOG,2-AMINOBICYCLO[2.1.1]HEXANE-2,5-DICARBOXYLIC ACID-I, A POTENT MGLUR AGONIST

To better characterize the roles of metabotropic glutamate receptors ( mGluRs) in physiological and pathophysiological processes, there is an important need to learn more about the structural features relevant t o the design of novel, high-affinity ligands that are family and subty pe specific. To date, many of the biological studies that have been co nducted in the area of mGluR research have made use of the agonist (1S ,3R)-ACPD. This compound has been shown to act as an agonist at both t he group I and group II receptors while showing little selectivity amo ng the four subtypes belonging to these two groups. Moreover, (1S,3S)- ACPD, the cis isomer, shows negligible activity at group I receptors a nd is a good agonist of mGluR2. Since ACPD is itself somewhat flexible , with four distinctive conformations being identified from molecular modeling studies for the trans isomer and five conformations for the c is isomer, we believed that it would be of interest to examine the act ivity of an ACPD analogue that has been constrained through the introd uction of a single carbon atom bridge. Accordingly, we have prepared a n aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACP D. The synthesis of this compound was accomplished by use of an intram olecular [2 + 2] photocycloaddition reaction, in which four distinct i somers were isolated. Of these four compounds, only a single isomer, A BHxD-I (6a), was found to be a potent agonist of the mGluRs. This comp ound, which expresses the fully extended glutamate conformation, was f ound to be more potent than ACPD at all six of the eight mGluR subtype s that were investigated and to be comparable to or more potent than t he endogenous ligand, glutamate, for these receptors. Interestingly, d espite its fixed conformation, ABHxD-I, like glutamate, shows little s ubtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S,3S)-ACPD, and L-glutamate, we conclude th at the aa conformation of L-glutamate is the active conformation for b oth group I and group II mGluRs. Moreover, the modeling-based comparis ons of these ligands suggest that the selectivity exhibited by LY35474 0 between the group I and group II mGluRs is not a consequence of diff erent conformations of L-glutamate being required for recognition at t hese mGluRs but rather is related to certain structural elements withi n certain regions having a very different impact on the group I and gr oup II mGluR activity. The enhanced potency of ABHxD-I relative to tra ns-ACPD commends it as a useful starting point in the design of subtyp e selective mGluR ligands.