Pesampator Explained

Pesampator (; developmental code names BIIB-104 and PF-04958242) is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by Pfizer for the treatment of cognitive symptoms in schizophrenia.^{[1] [2] [3]} It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness.^[4] As of July 2018, pesampator is in phase II clinical trials for cognitive symptoms in schizophrenia.

Pesampator belongs to the biarylpropylsulfonamide group of AMPAR PAMs, which also includes LY-404187, LY-503430, and mibampator (LY-451395) among others.^[5] It is described as a "high-impact" AMPAR PAM, unlike so-called "low-impact" AMPAR PAMs like CX-516 and its congener farampator (CX-691, ORG-24448). In animals, low doses of pesampator have been found to enhance cognition and memory, whereas higher doses produce motor coordination disruptions and convulsions. The same effects, as well as neurotoxicity at higher doses, have been observed with orthosteric and other high-impact allosteric AMPAR activators.

In healthy volunteers, pesampator has been found to significantly reduce ketamine-induced deficits in verbal learning and working memory without attenuating ketamine-induced psychotomimetic effects. It was able to complete reverse ketamine-induced impairments in spatial working memory in the participants.

In addition to its actions on the AMPAR, pesampator has been reported to act as a GlyT1 glycine transporter blocker.^{[6] [7]} As such, it is also a glycine reuptake inhibitor, and may act indirectly to activate the glycine receptor and the glycine co-agonist site of the NMDA receptor by increasing extracellular levels of glycine.

See also

• AMPA receptor positive allosteric modulator
• List of investigational antipsychotics

Notes and References

1. Shaffer CL, Patel NC, Schwarz J, Scialis RJ, Wei Y, Hou XJ, Xie L, Karki K, Bryce DK, Osgood SM, Hoffmann WE, Lazzaro JT, Chang C, McGinnis DF, Lotarski SM, Liu J, Obach RS, Weber ML, Chen L, Zasadny KR, Seymour PA, Schmidt CJ, Hajós M, Hurst RS, Pandit J, O'Donnell CJ . The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-ylpropane-2-sulfonamide (PF-04958242) . J. Med. Chem. . 58 . 10 . 4291–308 . 2015 . 25905800 . 10.1021/acs.jmedchem.5b00300 .
2. Ranganathan M, DeMartinis N, Huguenel B, Gaudreault F, Bednar MM, Shaffer CL, Gupta S, Cahill J, Sherif MA, Mancuso J, Zumpano L, D'Souza DC . Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242 . Mol. Psychiatry . 22. 11. 1633–1640. 2017 . 28242871 . 10.1038/mp.2017.6 . 3691566 .
3. Web site: PF 4958242. AdisInsight. 2017-08-30.
4. Bednar MM, DeMartinis N, Banerjee A, Bowditch S, Gaudreault F, Zumpano L, Lin FR . The Safety and Efficacy of PF-04958242 in Age-Related Sensorineural Hearing Loss: A Randomized Clinical Trial . JAMA Otolaryngol Head Neck Surg . 141 . 7 . 607–13 . 2015 . 25997115 . 10.1001/jamaoto.2015.0791 .
5. Froestl W, Muhs A, Pfeifer A . Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors . J. Alzheimers Dis. . 32 . 4 . 793–887 . 2012 . 22886028 . 10.3233/JAD-2012-121186 .
6. Singer P, Dubroqua S, Yee BK . Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy? . Curr. Pharm. Des. . 21 . 26 . 3771–87 . 2015 . 26205290 . 10.2174/1381612821666150724100952.
7. Mukherjea D, Ghosh S, Bhatta P, Sheth S, Tupal S, Borse V, Brozoski T, Sheehan KE, Rybak LP, Ramkumar V . Early investigational drugs for hearing loss . Expert Opin Investig Drugs . 24 . 2 . 201–17 . 2015 . 25243609 . 5488860 . 10.1517/13543784.2015.960076 .