Bay 36-7620

Metabotropic glutamate (mGlu) receptors are G proteincoupled receptors (GPCRs) that act predominantly as modulators of synaptic transmission. As such, they play a role in many physiological and pathophysiological processes. BAY36-7620 is a pPotent non-competitive mGlu1 receptor antagonist with.

In vitro: BAY36-7620 is a potent and selective antagonist at mGlu1receptors and inhibits >60% of mGlu1a receptor constitutive activity (IC50 = 0.38 μM). BAY36-7620 is thus the first described mGlu1 receptor inverse agonist. Moreover, BAY36-7620 did not displace the [3H]quisqualate binding from the Glu-binding pocket, indicating that BAY36-7620 is a noncompetitive mGlu1 antagonist [2].

In vivo: BAY 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse. As assessed in rats, BAY 36-7620 was devoid of the typical side effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and MK-801. Therefore, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulated behavior [3].

Clinical trial: Up to now, BAY 36-7620 is still in the preclinical development stage.

Reference:
[1] Carroll FY, Stolle A, Beart PM, Voerste A, Brabet I, Mauler F, Joly C, Antonicek H, Bockaert J, Müller T, Pin JP, Prézeau L.  BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol. 2001 May;59(5):965-73.
[2] De Vry J, Horváth E, Schreiber R.  Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620. Eur J Pharmacol. 2001 Oct 5;428(2):203-14.

The potent non-competitive mGlu1 receptor antagonist BAY 36-7620 differentially affects synaptic plasticity in area cornu ammonis 1 of rat hippocampal slices and impairs acquisition in the water maze task in mice.[Pubmed:18832015]

Neuroscience. 2008 Nov 19;157(2):385-95.

In this study we evaluated the effects of the novel, potent non-competitive metabotropic glutamate receptor (mGluR) 1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-o n (Bay 36-7620) on different types of synaptic plasticity in the hippocampal cornu ammonis (CA) 1-region and on hippocampus-dependent spatial learning. After having confirmed the presence of mGluR1 in the hippocampal CA1 region of our rat strain by confocal microscopy, we tested the effects of Bay 36-7620 on: 1) long-term potentiation (LTP) induced by weak and strong stimulation; 2) 3,5-dihydroxyphenylglycine (DHPG, 30 microM)-induced depression of synaptic transmission; and 3) learning of the hidden platform version of the water maze by mice. Bay 36-7620 (10 microM) amplified LTP but, like the mGluR1 antagonists 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt, 10 microM) and 4-carboxyphenylglycine (4-CPG, 50 microM), diminished LTP at 1 microM. The mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP, 10 microM) had no effect. Bay 36-7620 (10 microM) did not affect strong LTP. Thus, mGlu 1, but not mGlu 5, receptors modulate LTP elicited by weak stimulation in vitro. DHPG-induced depression of synaptic transmission was only marginally affected by Bay 36-7620 (1 microM) or 4-CPG (100 microM). In a mouse water maze study, Bay 36-7620 (10 mg/kg, i.v.) increased the escape latency and impaired water escape task acquisition during the first 4 days. Drug- and vehicle-treated groups showed comparable performance at day 5. Our data support a role for mGluR1 in LTP and in the acquisition of spatial memory.

Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620.[Pubmed:11675037]

Eur J Pharmacol. 2001 Oct 5;428(2):203-14.

This study characterized the neuroprotective and behavioral effects of (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (Bay 36-7620), a novel, selective and systemically active metabotropic glutamate (mGlu)(1) receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40-50% at 0.01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); whereas in the middle cerebral artery occlusion model, a trend for a neuroprotective effect was obtained after triple i.v. bolus application of 0.03-3 mg/kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those at which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. Bay 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse (MED: 10 mg/kg, i.v.). As assessed in rats, Bay 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801). Thus, Bay 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulation behavior. Although behavioral stereotypies and disruption of sensorimotor gating induced by amphetamine or apomorphine were not affected by Bay 36-7620, the compound attenuated some behavioral effects of iGlu receptor antagonists, such as excessive grooming or licking, and their facilitation of intracranial self-stimulation behavior. It is concluded that mGlu(1) receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resulting from antagonism of iGlu receptors.

Involvement of the mGluR1 receptor in hippocampal synaptic plasticity and associative learning in behaving mice.[Pubmed:18024992]

Cereb Cortex. 2008 Jul;18(7):1653-63.

Metabotropic glutamate receptor 1 (mGluR1) has been related to processes underlying learning in hippocampal circuits, but demonstrating its involvement in synaptic plasticity when measured directly on the relevant circuit of a learning animal has proved to be technically difficult. We have recorded the functional changes taking place at the hippocampal CA3-CA1 synapse during the acquisition of an associative task in conscious mice carrying a targeted disruption of the mGluR1 gene. Animals were classically conditioned to evoke eyelid responses, using a trace (conditioned stimulus [CS], tone; unconditioned stimulus [US], electric shock) paradigm. Acquisition of this task was impaired in mutant mGluR1(+/-) mice and abolished in mGluR1(-/-) mice. A single pulse presented to Schaffer collaterals during the CS-US interval evoked a monosynaptic field excitatory postsynaptic potential at ipsilateral CA1 pyramidal cells, whose slope was linearly related to learning evolution in controls but not in mGluR1 mutants. Long-term potentiation evoked by train stimulation of Schaffer collaterals was also impaired in both mGluR1(+/-) and mGluR1(-/-) animals. Administration of the selective mGluR1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental [c]furan-1-on to wild-type animals mimicked the functional changes associated to mGluR1 insufficiency in mutants. Thus, mGluR1 is required for activity-dependent synaptic plasticity and associative learning in behaving mice.

BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity.[Pubmed:11306677]

Mol Pharmacol. 2001 May;59(5):965-73.

L-Glutamate (Glu) activates at least eight different G protein-coupled receptors known as metabotropic glutamate (mGlu) receptors, which mostly act as regulators of synaptic transmission. These receptors consist of two domains: an extracellular domain in which agonists bind and a transmembrane heptahelix region involved in G protein activation. Although new mGlu receptor agonists and antagonists have been described, few are selective for a single mGlu subtype. Here, we have examined the effects of a novel compound, BAY36-7620 [(3aS,6aS)- 6a-Naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on], on mGlu receptors (mGlu1-8), transiently expressed in human embryonic kidney 293 cells. BAY36-7620 is a potent (IC(50) = 0.16 microM) and selective antagonist at mGlu1 receptors and inhibits >60% of mGlu1a receptor constitutive activity (IC(50) = 0.38 microM). BAY36-7620 is therefore the first described mGlu1 receptor inverse agonist. To address the mechanism of action of BAY36-7620, Glu dose-response curves were performed in the presence of increasing concentrations of BAY36-7620. The results show that BAY36-7620 largely decreases the maximal effect of Glu. Moreover, BAY36-7620 did not displace the [(3)H]quisqualate binding from the Glu-binding pocket, further indicating that BAY36-7620 is a noncompetitive mGlu1 antagonist. Studies of chimeric receptors containing regions of mGlu1 and regions of DmGluA, mGlu2, or mGlu5, revealed that the transmembrane region of mGlu1 is necessary for activity of BAY36-7620. Transmembrane helices 4 to 7 are shown to play a critical role in the selectivity of BAY36-7620. This specific site of action of BAY36-7620 differs from that of competitive antagonists and indicates that the transmembrane region plays a pivotal role in the agonist-independent activity of this receptor. BAY36-7620 will be useful to further delineate the functional importance of the mGlu1 receptor, including its putative agonist-independent activity.