LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization

Verma, Mahip K.; Goel, Rajan; Bokare, Anand M.; Dandekar, Manoj P.; Koul, Sarita; Desai, Sumit; Tota, Santoshkumar; Singh, Nitya; Nigade, Prashant B.; Patil, Vinod; Modi, Dipak; Mehta, Maneesh; Gundu, Jayasagar; Walunj, Sameer S.; Karche, Navnath P.; Sinha, Neelima; Kamboj, Rajender K.; Palle, Venkata P.

doi:10.1016/j.ejphar.2020.173685

Cited by 5 publications

(6 citation statements)

References 67 publications

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“…A close structural analog, LL-00066471 (a type II PAM), shows high potency (EC 50 = 0.49 μM at the hα7), and good brain permeability with a brain:plasma ratio around 1.5 in rats. LL-00066471 demonstrated high efficacy in animal models of cognitive and sensorimotor-gating deficits, supporting its potential use in the treatment of cognitive impairments associated with neurological and psychiatric conditions [ 76 , 77 ]. At Gedeon Richter Plc., A-867744 has been extensively modified to discover novel α7-PAMs.…”

Section: α7 Pamsmentioning

confidence: 99%

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

et al. 2023

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Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4β2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the design of selective modulators. Experimental evidence supports the use of allosteric modulators as therapeutic tools for neurological and non-neurological conditions.

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Section: α7 Pamsmentioning

confidence: 99%

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

et al. 2023

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“…a7 PAMs have been shown to be active in many of the same animal models that have been used with the identification of a7-selective agonists. For example, LL-00066471 (Verma et al, 2021) and BNC375 (Wang et al, 2020b) were shown to improve performance in novel object recognition (NOR) and other cognitive tests. Likewise, RO5126946 (Sahdeo et al, 2014), NS1738 (Timmermann et al, 2007), and Lu AF58801, (1S,2S)-2phenyl-cyclopropanecarboxylic acid [a(R)-(4-ethoxy-phenyl)-2-hydroxy-ethyl]-amide (Eskildsen et al, 2014) were also active in cognitive tests, and BNC375 enhanced long-term potentiation (Wang et al, 2020b).…”

Section: A7-positive Allosteric Modulatorsmentioning

confidence: 99%

Therapeutic Targeting of α7 Nicotinic Acetylcholine Receptors

Papke

Horenstein

2021

Pharmacol Rev

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“…It has been proposed that this could be due to the fact that nicotine improves cognition in schizophrenic patients [ 159 , 160 ]. Indeed, it has been widely described that α 7 nicotinic acetylcholine receptor activators have a beneficial procognitive effect both in animal models of schizophrenia [ 161 , 162 ] and in patients, although modulation of nicotinic receptors in humans entails a high risk of adverse events [ 163 ]. The reason for the beneficial effect of α 7 nicotinic acetylcholine receptor activators on cognitive deficit is complex.…”

Section: Treatment Of Cognitive Deficit In Schizophreniamentioning

confidence: 99%

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments

Martínez

Brea

Rico

et al. 2021

IJMS

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Schizophrenia is a major mental illness characterized by positive and negative symptoms, and by cognitive deficit. Although cognitive impairment is disabling for patients, it has been largely neglected in the treatment of schizophrenia. There are several reasons for this lack of treatments for cognitive deficit, but the complexity of its etiology—in which neuroanatomic, biochemical and genetic factors concur—has contributed to the lack of effective treatments. In the last few years, there have been several attempts to develop novel drugs for the treatment of cognitive impairment in schizophrenia. Despite these efforts, little progress has been made. The latest findings point to the importance of developing personalized treatments for schizophrenia which enhance neuroplasticity, and of combining pharmacological treatments with non-pharmacological measures.

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LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization

Cited by 5 publications

References 67 publications

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

Therapeutic Targeting of α7 Nicotinic Acetylcholine Receptors

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments

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