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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Bioactivity Comments |
T-495 does not compete for scopolamine binding to M1R indicating that it binds to an allosteric site. It has weak but measurable agonist activity in CHO‐K1 cells expressing human M1R, in the absence of acetylcholine. |
Selectivity at GPCRs | ||||||||||||||||||||||||||||||||||
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