Synthesis and Biology of the Conformationally Restricted ACPD Analogue, 2-Aminobicyclo[2.1.1]hexane-2,5-dicarboxylic Acid-I, a Potent mGluR Agonist

Abstract

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 to the design of novel, high-affinity ligands that are family and subtype specific. To date, many of the biological studies that have been conducted 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 the group I and group II receptors while showing little selectivity among the four subtypes belonging to these two groups. Moreover, (1S,3S)-ACPD, the cis isomer, shows negligible activity at group I receptors and 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 cis isomer, we believed that it would be of interest to examine the activity of an ACPD analogue that has been constrained through the introduction of a single carbon atom bridge. Accordingly, we have prepared an aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACPD. The synthesis of this compound was accomplished by use of an intramolecular [2 + 2] photocycloaddition reaction, in which four distinct isomers were isolated. Of these four compounds, only a single isomer, ABHxD-I (6a), was found to be a potent agonist of the mGluRs. This compound, which expresses the fully extended glutamate conformation, was found to be more potent than ACPD at all six of the eight mGluR subtypes that were investigated and to be comparable to or more potent than the endogenous ligand, glutamate, for these receptors. Interestingly, despite its fixed conformation, ABHxD-I, like glutamate, shows little subtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S, 3S)-ACPD, and l-glutamate, we conclude that the aa conformation of l-glutamate is the active conformation for both group I and group II mGluRs. Moreover, the modeling-based comparisons of these ligands suggest that the selectivity exhibited by LY354740 between the group I and group II mGluRs is not a consequence of different conformations of L-glutamate being required for recognition at these mGluRs but rather is related to certain structural elements within certain regions having a very different impact on the group I and group II mGluR activity. The enhanced potency of ABHxD-I relative to trans-ACPD commends it as a useful starting point in the design of subtype selective mGluR ligands.

l-Homocysteine Sulfinic Acid and Other Acidic Homocysteine Derivatives Are Potent and Selective Metabotropic Glutamate Receptor Agonists

“…Cell lines stably transfected with recombinant cDNA encoding receptors or cell lines that express endogenous receptors were used for the drug screen. The recombinant cDNA included 1) human adrenergic receptors, ␣ 1A , ␣ 1B , ␣ 2A , ␣ 2B , ␣ 2C , and rat adrenergic receptors, ␤ 1 and ␤ 2 ; 2) rat cannabanoid CB1 receptor; 3) dopaminergic receptors, hD1, hD2, hD3, rD4, and hD5; 4) human histamine receptors, H1, H2, and H4; 5) rat imidazoline receptor; 6) human muscarinic acetylcholine receptors, M1, M2, M3, M4, and M5; 7) human nicotinic acetylcholine receptors, ␣ 2 /␤ 2 , ␣ 2 /␤ 4 , ␣ 3 /␤ 2 , ␣ 3 /␤ 4 , ␣ 4 /␤ 2 , and ␣ 4 /␤ 4 ; 8) human opiate receptors, , ␦, and ; 9) human peptide receptors, V1, V2, V3, and OT; 10) serotonergic receptors, h5-HT1A, h5-HTB, h5-HTD, r5-HT2A, r5-HT2C, h5-HT3, h5-HT5A, h5-HT6, and h5-HT7; 11) human transporters of serotonin, norepinephrine, and dopamine as previously described (Roth et al, 1998(Roth et al, , 2001Rothman et al, 2000;Shapiro et al, 2002); and 12) rat metabotropic glutamate receptors, mGluR1a, mGluR2, mGluR4, mGluR5a, mGluR6, and mGluR8 as previously described (Gomeza et al, 1996;Wroblewska et al, 1997;Kozikowski et al, 1998). The endogenous receptors included 1) GABA receptors, GABA A , GABA B , and GABA BZP from rat forebrain; 2) histamine receptor H1 from rat forebrain; 3) rat nicotinic acetylcholine receptor, ␣ 4 /␤ 2 ; 4) ionotropic glutamate receptor NMDA from rat forebrain; and 5) voltage-sensitive Ca 2ϩ channel from rat heart.…”

Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

“…Cell lines stably transfected with recombinant cDNA encoding receptors or cell lines that express endogenous receptors were used for the comprehensive screening using the resources of the National Institute of Mental Health's Psychoactive Drug Screening Program (PDSP) as previously detailed . The recombinant receptors included (1) human adrenergic receptors, a1A, a1B, a2A, a2B, a2C, and rat adrenergic receptors, b1 and b2; (2) rat cannabanoid CB1 receptor; (3) dopaminergic receptors, hD1, rD2, rD3, rD4, and hD5; (4) human histamine receptors, H1, H2, and H4; (5) rat imidazoline receptor; (6) human muscarinic acetylcholine receptors, M1, M2, M3, M4, and M5; (7) human nicotinic acetylcholine receptors, a2/b2, a2/b4, a3/b2, a3/b4, a4/b2, and a4/b4; (8) human opiate receptors, m, d, and k; (9) human peptide receptors, V1, V2, V3, and OT; (10) serotonergic receptors, h5-HT1A, r5-HT1B, h5-HT1E, r5-HT2A, h5-HT2B, r5-HT2C, h5-HT3, h5-HT5A, h5-HT6, and h5-HT7; (11) human transporters of serotonin, norepinephrine, and dopamine as previously described (Roth et al, 1998;Rothman et al, 2000;Roth et al, 2001;Roth et al, 2002;Shapiro et al, 2002); and (12) rat metabotropic glutamate receptors, mGluR1a, mGluR2, mGluR4, mGluR5a, mGluR6, and mGluR8 as previously described (Gomeza et al, 1996;Wroblewska et al, 1997;Kozikowski et al, 1998;Shi et al, 2003). The endogenous receptors included (1) GABA receptors, GABA A , GABA B , and GABA BZP from rat forebrain; (2) histamine receptor H1 from rat forebrain; (3) rat nicotinic acetylcholine receptor, a4/b2; (4) ionotropic NMDA glutamate receptor from rat forebrain; and (5) voltage-sensitive Ca 2 þ channel from rat heart.…”

Neuroimaging - Clinical Applications

“…The second type of receptors are the G-protein or second messenger-linked 'metabotropic' EAA receptors. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increase or decrease in cAMP formation, and changes in ion channel function (Kozikowski et al, 1998). Metabotropic glutamate receptors belong to Class C of a superfamily of G-protein coupled receptors (GPCRs).…”