VU-0238429 explained

VU-0238429 is a drug which acts as a selective positive allosteric modulator for the muscarinic acetylcholine receptor M₅. It was the first selective ligand developed for the M₅ subtype,^[1] and is structurally derived from older M₁-selective positive allosteric modulators such as VU-0119498.^{[2] [3]} Replacing the O-methyl- by a phenyl group further improves the receptor subtype selectivity.^[4]

Notes and References

1. Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW . 6 . Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins . Journal of Medicinal Chemistry . 52 . 11 . 3445–3448 . June 2009 . 19438238 . 3875304 . 10.1021/jm900286j .
2. Conn PJ, Jones CK, Lindsley CW . Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders . Trends in Pharmacological Sciences . 30 . 3 . 148–155 . March 2009 . 19201489 . 2907736 . 10.1016/j.tips.2008.12.002 .
3. Bridges TM, Kennedy JP, Hopkins CR, Conn PJ, Lindsley CW . Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators . Bioorganic & Medicinal Chemistry Letters . 20 . 19 . 5617–5622 . October 2010 . 20801651 . 3179183 . 10.1016/j.bmcl.2010.08.042 .
4. Bridges TM, Phillip Kennedy J, Noetzel MJ, Breininger ML, Gentry PR, Conn PJ, Lindsley CW . Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM . Bioorganic & Medicinal Chemistry Letters . 20 . 6 . 1972–1975 . March 2010 . 20156687 . 2834874 . 10.1016/j.bmcl.2010.01.109 .