Synonyms: example 24 [WO2016208775] | T495
Compound class:
Synthetic organic
Comment: T-495 is a positive allosteric modulator (PAM) of the M1 muscarinic acetylcholine receptor [1]. It was designed as a low-cooperativity PAM which was predicted to reduce the gastrointestinal (GI) side-effects (principally diarrhea) that are caused by M1R activation in the ileum, whilst retaining efficacy to improve cognitive deficits in animal models. The measure of allosteric cooperativity (α-value) of T-495 is 199. In contrast the α-value for MK-7622 is 511, indicating that this PAM more effectively increases agonist activity at the receptor than T-495. In vivo, T‐495 exhibits a wider margin between memory improvement and induction of diarrhea than MK‐7622 in rats, suggesting that the hypothesis re low PAM cooperativity and reduced GI adverse reaction was valid. T-495 effectively reverses memory deficits in a mouse model of dementia with Lewy bodies and Parkinson's disease in which acetylcholine levels are reduced.
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