Disease relevance of CB 1712

• The role of metabotropic excitatory amino acid receptors in seizures and brain injury was examined using the selective metabotropic agonist 1S,3R-ACPD [(1S,3R)-1-aminocyclopentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats [1].
• Activation of metabotropic glutamate receptors (mGluRs) with 1-aminocyclopentane-1S,3R-dicarboxylic acid 20 min prior to tetanus facilitates, or "primes," subsequent induction of long-term potentiation (LTP; Cohen and Abraham, J Neurophysiol 1996;76:953-962) [2].
• Pretreatment with the metabotropic glutamate receptor agonists (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) 1 h before anoxia or NO exposure increased hippocampal neuronal cell survival from approximately 30 to 70% [3].
• We have recently reported that, in rat dorsolateral septal nucleus (DLSN) neurones, a 1S,3R-ACPD-preferring inward current (ACPDi) persists in pertussis toxin-treated rats [4].
• MK-801 (0.08, 0.16, 0.32 mg/kg i.p.) as well as D,L-amphetamine (1.0, 2.0, 3.0 mg/kg i.p.) potently reversed 1S,3R-ACPD-induced (80 micrograms) catalepsy [5].

Psychiatry related information on CB 1712

• The analysis of motor activity showed that 3,5-DHPG elicited higher central stimulatory action than did 1S,3R-ACPD [6].
• This effect of 1S,3R-ACPD was markedly attenuated by both repeated imipramine and electroconvulsive shock treatment, and the action of (R,S)-3,5-DHPG was markedly attenuated by prolonged imipramine treatment (electroconvulsive shock was not tested) [7].

High impact information on CB 1712

• We have shown that the mGluR agonist (1S,3R)-1-amino-1, 3-cyclopentanedicarboxylic acid (1S,3R-ACPD) has multiple actions on phrenic motoneurons (PMNs), including reduction of inspiratory-modulated synaptic currents and an increase of neuronal excitability [8].
• Multiple actions of 1S,3R-ACPD in modulating endogenous synaptic transmission to spinal respiratory motoneurons [9].
• (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), an agonist for metabotropic glutamate receptors (mGluRs), causes depolarization and burst firing in rat dorsolateral septal nucleus (DLSN) neurons and results in long-term potentiation (LTP) at DLSN synapses [10].
• The metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3 dicarboxylic acid (ACPD) at concentrations above 60 microM produced stereotypic oscillatory activity in CA3 pyramidal cells of rat hippocampal slices [11].
• In the presence of the selective mGluR agonist 1S,3R-1-aminocyclopentane-1,3- dicarboxylic acid (1S,3R-ACPD; 5-200 microM), both excitatory and inhibitory components of the evoked PSPs were reversibly reduced [12].

Chemical compound and disease context of CB 1712

• In the absence of adenosine A2 receptor blockade, the mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) stimulated cAMP accumulation through a pertussis toxin-insensitive mechanism that could be blocked by L-serine-o-phosphate, but not by L(+)-2-amino-3-phosphonopropionic acid [13].
• (1S,3R)-1-carboxycyclopentane-3-acetic acid (1S,3R-ACPD), a nonselective mGlu receptor agonist, caused a concentration-dependent increase in inositol phosphate in slices from the CA1 region of the hippocampus, an effect that was not modified by imipramine or electroconvulsive shock treatment [7].

Biological context of CB 1712

• There was no correlation between levels of mGluR mRNA and stimulation of polyphosphoinositide hydrolysis by 1-aminocyclopentane-1S,3R-dicarboxylic acid (trans-ACPD), which was much greater in brain slices from 8-day-old rats and was nearly absent in the adult cerebellum and olfactory bulb, where we have found the highest levels of mRNA [14].
• Stimulations of cAMP content evoked by 1S,3R-ACPD and combined additions of DHPG plus 2R,4R-APDC occurred at concentrations of these agents that directly couple to other mGluR second messenger responses [15].
• Activation of metabotropic glutamate receptors with (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid significantly increased phosphorylation of MAP-2 in control neurons, whereas in neurons exposed to ammonia the response was the opposite, with 1-aminocyclopentane-1,3-dicarboxylic acid inducing a dephosphorylation of MAP-2 [16].
• The expression of mGlu5a receptor mRNA and the occurrence of 1S,3R-ACPD-induced calcium signaling were found also in cultured microglia, indicating for the first time expression of mGlu5a receptors in these macrophage-like cells [17].
• The mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) prevented the development of low K(+)-induced apoptosis and the presence of the drug was critical at 6 and 7 DIV, i.e., after the drop of mGluR activity [18].

Anatomical context of CB 1712

• To determine physiological roles of metabotropic glutamate receptors (mGluRs) affecting breathing, we examined the effects of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) on synaptic transmission and excitability of phrenic motoneurons (PMNs) in an in vitro neonatal rat brainstem/spinal cord preparation [9].
• Thus, 1S,3R-ACPD-induced increases in cAMP formation in the neonatal rat hippocampus are mediated by a synergistic interaction between mGluRs coupled to phosphoinositide (group 1) and inhibitory cAMP (group 2), which are indirectly expressed by potentiation of cAMP responses to other agonists (in this case, endogenous adenosine) [15].
• A similar development pattern of modulation was observed in hypothalamic slices with the difference that 1S,3R-ACPD did not stimulate basal cAMP formation in the hypothalamus of adult animals [19].
• Single-cell [Ca2+]i recordings indicated that an mGluR-selective agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), elicits [Ca2+]i oscillations in good agreement with the growth factor-induced up-regulation of mGluR5 in cultured astrocytes [20].
• At higher doses (15-25 microM) 1S,3R-ACPD produced a direct depolarization of Purkinje cells in 58% of cells examined [21].

Associations of CB 1712 with other chemical compounds

• In rats, unilateral striatal injection of the nonsubtype selective mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) results in contralateral rotation with delayed onset, thought to be secondary to an increase in dopamine release [22].
• The mGluR agonists t-ACPD and 1S,3R-ACPD produced a reversible and dose-dependent decrease of both HVA Ca2+ currents and GABA-mediated synaptic potentials [23].
• Exposure to putative mGluR antagonists, alpha-methyl-4-carboxyphenylglycine or L-2-amino-3-phosphonopropionic acid, did not inhibit the 1S,3R-ACPD-mediated effect [12].
• Responses to 1S,3R-ACPD were occluded by prior activation of L-AP4 receptors, but not blocked by the non-AP4, mGluR antagonists, L-aminophosphonopropionic acid (L-AP3) or 4-carboxy-3-hydroxyphenylglycine (4C3H-PG) [24].
• In vitro studies on agonist-induced brain phosphoinositide hydrolysis have shown that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid is a highly selective and efficacious metabotropic EAA agonist [25].

Gene context of CB 1712

• The mGlu receptor subtypes and second messenger pathways that mediate 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) responses in brain tissues are not fully understood [26].
• Application of the selective metabotropic glutamate receptor (mGluR) agonist 1S,3R-ACPD induced a transient depression followed by a rapid onset LTP of both the AMPAR and the NMDAR components of the dual component EPSC [27].
• Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3 [28].
• The response to (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid was inhibited by the mGluR antagonist (S)-alpha-methyl-4-carboxyphenylglycine and, less potently, by 1-aminoindan-1,5-dicarboxylic acid and 4-carboxyphenylglycine, two antagonists of group I mGluRs that display higher potency on mGluR1 than on mGluR5 [29].
• Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin-stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3 [30].

Analytical, diagnostic and therapeutic context of CB 1712

• Perfusion of the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) for a prolonged period (20 min) induced long-term depression (LTD) of field excitatory postsynaptic field potentials (epsps) from the baseline level and also depotentiation (DP) from the long-term potentiated level [31].
• 2. With CsCl-filled microelectrodes, bath application of 1S,3R-ACPD induced an inward current of -308 +/p 50 (SE) pA amplitude [holding potential (VH -60 mV, n = 12)] associated with a conductance decrease (26.5 +/- 5.6%, P < or = 0.0022, n = 12) [32].
• 1S,3R-ACPD-induced LTP does not require electrical stimulation during its induction, but is dependent on an intact connection between the CA3 and CA1 regions of the hippocampus [33].
• 1. The single-electrode voltage-clamp technique was used to study the effects of the metabotropic glutamate receptors (mGluRs) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, ACPD, 3-10 microM) on CA3 hippocampal neurons during the 1st 10 days of postnatal (P) life and in adulthood [34].
• The Group II and Group III mGluR agonists L-AP4, CCG-I, DCG-IV, 1S,3R-ACPD and S-4C3HPG, applied in the vicinity of the recording site by iontophoresis, were found to reduce inhibitions revealed by the condition-test paradigm (by 67, 75, 50, 43 and 77% from control inhibitions, respectively) [35].

References