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Chemical compound
Pesampator
Other names BIIB-104; PF-04958242
N -[(3S ,4S )-4-[4-(5-cyanothiophen-2-yl)phenoxy]oxolan-3-yl]propane-2-sulfonamide
CAS Number
PubChem
CID
ChemSpider
UNII
CompTox Dashboard (
EPA )
Formula C 18 H 20 N 2 O 4 S 2
Molar mass 392.49 g·mol−1 3D model (
JSmol )
CC(C)S(=O)(=O)N[C@H]1COC[C@H]1OC2=CC=C(C=C2)C3=CC=C(S3)C#N
InChI=1S/C18H20N2O4S2/c1-12(2)26(21,22)20-16-10-23-11-17(16)24-14-5-3-13(4-6-14)18-8-7-15(9-19)25-18/h3-8,12,16-17,20H,10-11H2,1-2H3/t16-,17+/m0/s1
Key:TTYKUKSFWHEBLI-DLBZAZTESA-N
Pesampator (
INN Tooltip International Nonproprietary Name ; 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.
[3]
[4] As of July 2018, pesampator is in
phase II
clinical trials for cognitive symptoms in schizophrenia.
[3]
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).
[2] In animals, low doses of pesampator have been found to enhance
cognition and
memory , whereas higher doses produce
motor coordination
disruptions and
convulsions .
[2] The same effects, as well as
neurotoxicity at higher doses, have been observed with
orthosteric and other high-impact
allosteric AMPAR activators.
[2]
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.
[2] It was able to complete reverse ketamine-induced impairments in
spatial working memory in the participants.
[2]
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 .
[6]
[7]
See also
References
^ 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 (2015). "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-yl}propane-2-sulfonamide (PF-04958242)". J. Med. Chem . 58 (10): 4291–308.
doi :
10.1021/acs.jmedchem.5b00300 .
PMID
25905800 .
^
a
b
c
d
e
f 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 (2017). "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.
doi :
10.1038/mp.2017.6 .
PMID
28242871 .
S2CID
3691566 .
^
a
b
c
"PF 4958242" . AdisInsight . Retrieved 2017-08-30 .
^ Bednar MM, DeMartinis N, Banerjee A, Bowditch S, Gaudreault F, Zumpano L, Lin FR (2015). "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.
doi :
10.1001/jamaoto.2015.0791 .
PMID
25997115 .
^ Froestl W, Muhs A, Pfeifer A (2012). "Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors". J. Alzheimers Dis . 32 (4): 793–887.
doi :
10.3233/JAD-2012-121186 .
PMID
22886028 .
^
a
b Singer P, Dubroqua S, Yee BK (2015). "Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?". Curr. Pharm. Des . 21 (26): 3771–87.
doi :
10.2174/1381612821666150724100952 .
PMID
26205290 .
^
a
b Mukherjea D, Ghosh S, Bhatta P, Sheth S, Tupal S, Borse V, Brozoski T, Sheehan KE, Rybak LP, Ramkumar V (2015).
"Early investigational drugs for hearing loss" . Expert Opin Investig Drugs . 24 (2): 201–17.
doi :
10.1517/13543784.2015.960076 .
PMC
5488860 .
PMID
25243609 .
Receptor (
ligands )
GlyR Tooltip Glycine receptor
Positive modulators:
Alcohols (e.g.,
brometone ,
chlorobutanol (chloretone) ,
ethanol (alcohol) ,
tert -butanol (2M2P) ,
tribromoethanol ,
trichloroethanol ,
trifluoroethanol )
Alkylbenzene sulfonate
Anandamide
Barbiturates (e.g.,
pentobarbital ,
sodium thiopental )
Chlormethiazole
D12-116
Dihydropyridines (e.g.,
nicardipine )
Etomidate
Ginseng constituents (e.g.,
ginsenosides (e.g.,
ginsenoside-Rf ))
Glutamic acid (glutamate)
Ivermectin
Ketamine
Neuroactive steroids (e.g.,
alfaxolone ,
pregnenolone (eltanolone) ,
pregnenolone acetate ,
minaxolone ,
ORG-20599 )
Nitrous oxide
Penicillin G
Propofol
Tamoxifen
Tetrahydrocannabinol
Triclofos
Tropeines (e.g.,
atropine ,
bemesetron ,
cocaine ,
LY-278584 ,
tropisetron ,
zatosetron )
Volatiles /
gases (e.g.,
chloral hydrate ,
chloroform ,
desflurane ,
diethyl ether (ether) ,
enflurane ,
halothane ,
isoflurane ,
methoxyflurane ,
sevoflurane ,
toluene ,
trichloroethane (methyl chloroform) ,
trichloroethylene )
Xenon
Zinc
Antagonists:
2-Aminostrychnine
2-Nitrostrychnine
4-Phenyl-4-formyl-N-methylpiperidine
αEMBTL
Bicuculline
Brucine
Cacotheline
Caffeine
Colchicine
Colubrine
Cyanotriphenylborate
Dendrobine
Diaboline
Endocannabinoids (e.g.,
2-AG ,
anandamide (AEA) )
Gaboxadol (THIP)
Gelsemine
iso-THAZ
Isobutyric acid
Isonipecotic acid
Isostrychnine
Laudanosine
N-Methylbicuculline
N-Methylstrychnine
N,N-Dimethylmuscimol
Nipecotic acid
Pitrazepin
Pseudostrychnine
Quinolines (e.g.,
4-hydroxyquinoline ,
4-hydroxyquinoline-3-carboxylic acid ,
5,7-CIQA ,
7-CIQ ,
7-TFQ ,
7-TFQA )
RU-5135
Sinomenine
Strychnine
Thiocolchicoside
Tutin
Negative modulators:
Amiloride
Benzodiazepines (e.g.,
bromazepam ,
clonazepam ,
diazepam ,
flunitrazepam ,
flurazepam )
Corymine
Cyanotriphenylborate
Daidzein
Dihydropyridines (e.g.,
nicardipine ,
nifedipine ,
nitrendipine )
Furosemide
Genistein
Ginkgo constituents (e.g.,
bilobalide ,
ginkgolides (e.g.,
ginkgolide A ,
ginkgolide B ,
ginkgolide C ,
ginkgolide J ,
ginkgolide M ))
Imipramine
NBQX
Neuroactive steroids (e.g.,
3α-androsterone sulfate ,
3β-androsterone sulfate ,
deoxycorticosterone ,
DHEA sulfate ,
pregnenolone sulfate ,
progesterone )
Opioids (e.g.,
codeine ,
dextromethorphan ,
dextrorphan ,
levomethadone ,
levorphanol ,
morphine ,
oripavine ,
pethidine ,
thebaine )
Picrotoxin (i.e.,
picrotin and
picrotoxinin )
PMBA
Riluzole
Tropeines (e.g.,
bemesetron ,
LY-278584 ,
tropisetron ,
zatosetron )
Verapamil
Zinc
NMDAR Tooltip N-Methyl-D-aspartate receptor
Transporter (
blockers )
GlyT1 Tooltip Glycine transporter 1
GlyT2 Tooltip Glycine transporter 2
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KAR Tooltip Kainate receptor
NMDAR Tooltip N-Methyl-D-aspartate receptor