Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition

Abstract

In the current study we compared the potency of the selective metabotropic glutamate receptor (mGluR1) antagonist A-841720 (7-Azepan-1-yl-4-dimethylamino-7H-9-thia-1,5,7-triaza-fluoren-8-one) in rodent models of pain with its effects in models of learning and memory, to obtain information regarding the therapeutic window of this compound. A-841720 significantly reduced formalin-induced behaviours and complete Freund's adjuvant (CFA)-induced tactile allodynia, starting at doses of 1 and 10 mg/kg, respectively. At the dose of 3 mg/kg, however, A-841720 significantly reduced the percentage of spontaneous alternations in a radial-maze task. In contextual-fear conditioning, A-841720, given at the dose of 10 mg/kg before acquisition, significantly reduced freezing behaviour tested 24 h later. In the same task, repeated treatment for 5 days did not reduce the impairing effect of the challenge dose, indicating a lack of tolerance development. In a passive-avoidance task, A-841720 at 10 mg/kg administered before acquisition, significantly reduced the latency to enter the dark box on the retention test. Given that complete Freund's adjuvant is a better measure of analgesia, these results indicate that the selective mGluR1 antagonist A-841720 has analgesic potential in a dose range at which it also produces memory impairments. This diminishes its therapeutic potential for the treatment of chronic pain.

Recent Advances in the Medicinal Chemistry of the Metabotropic Glutamate Receptor 1 (mGlu1)

“…REVIEW without supporting patents, suggests that there may be a mechanistic safety issue with mGlu 1 antagonism. This is supported by independent reports from Johnson and Johnson, 29 Pfizer, 30 Merz, 31 and Abbott 32 related to behavioral side effects and low therapeutic indecies for a range of structurally differentiated mGlu 1 chemotypes. Johnson and Johnson 29 reported that full occupancy of mGlu 1 reeceptors in the cerebellum and thalamus is associated with acquisition and retention impairment in a spatial water maze task.…”

“…Merz and Abbott both profiled A-841720 in pain efficacy models while also assessing motor and cognitive function side effects. 31,32 A-841720 worked at doses beginning at 1 mg/kg in the CFA pain model, going on to give full efficacy at 10 mg/kg. However, significant motor side effects were seen at these analgesic doses with the compound causing impaired cognitive function in water maze tests.…”

“…Johnson and Johnson reported that full occupancy of mGlu 1 reeceptors in the cerebellum and thalamus is associated with acquisition and retention impairment in a spatial water maze task. Merz and Abbott both profiled A-841720 in pain efficacy models while also assessing motor and cognitive function side effects. , A-841720 worked at doses beginning at 1 mg/kg in the CFA pain model, going on to give full efficacy at 10 mg/kg. However, significant motor side effects were seen at these analgesic doses with the compound causing impaired cognitive function in water maze tests.…”

Synergy between vesicular and non-vesicular gliotransmission regulates synaptic plasticity and working memory

“…A classical 8-radial arm maze for mice (More et al, 2008;More et al, 2007) was placed on the water tank with 4 out 8 arms kept open to form a cross. Each mouse was singly released in the centre of the maze and tracked for 10 minutes with AnyMaze4.99 tracking software.…”

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

“…-N-methyl-N-[4-[6-(propan-2ylamino)pyrimidin-4-yl]-1,3-thiazol-2Union of Pure and Applied Chemistry; MoA, mechanism of action; pK B , negative logarithm of the equilbrium dissociation constant for an allosteric ligand; pEC 50 , negative logarithm of the agonist or PAM concentration required to give the half-maximal response (activation or potentiation); pIC 50 , negative logarithm of the NAM concentration required to give the half-maximal inhibition.a Where affinity estimates were unavailable pIC 50 (NAMs) or pEC 50 (PAMs) values are reported indicated by italics. b 1)Zheng et al, 2005;El-Kouhen et al, 2006;Morè et al, 2007;Zhu et al, 2008. 2) Carroll et al, 2001De Vry et al, 2001;Lavreysen et al, 2003;Schröder et al, 2008;Cho et al, 2014a.…”