Phenylethanolamine-based NMDA receptor antagonists
Described herein are enhanced N-methyl-D-aspartate (NMDA) receptor antagonists, pharmaceutical compositions thereof, and their methods of use and treatment, e.g., of Formula (I): wherein one or more of R 1 , R 2 , R 3 , R 4 , R 5 , or the ring formed by the joining of R 1 and R 2 , is a hydrophobic moiety which confers enhanced antagonist activity as compared to existing NMDA receptor antagonists, e.g., ifenprodil. Compounds described herein are designed based on the discovery that ifenprodil binds within the allosteric domain of the GluN1/GluN2B NMDA receptor, particularly at the interface between GluN1 and GluN2B subunits. In silico methods are further described herein.
1. A compound of Formula (I-c):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH;
each instance of R 6 is independently selected from the group consisting of substituted hydroxyl, substituted thio, silyl, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, provided at least two R 6 groups ortho to each other are joined to form an optionally substituted pyrrolyl ring;
x is an integer between 2 and 5, inclusive;
y is 0 or 1; and
m is 1 or 2;
wherein the compound stabilizes the molecular conformation of hydrophobic residues GluN1b A74, GluN2B I82, and GluN2B F114 of the NMDA receptor.
2. The compound of claim 1 , wherein the compound physically interacts with the hydrophobic residues GluN1b A74, GluN2B I82, and GluN2B F114 of the NMDA receptor, thereby partially or completely inhibiting NMDA receptor function.
3. The compound of claim 1 , wherein the compound is of formula (I-f):
or a pharmaceutically acceptable salt thereof,
wherein the two R 6 groups ortho to each other are joined to form an optionally substituted pyrrolyl ring.
4. The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.