PCP site 2

PCP site 2 is a binding site that was identified as a high-affinity target for phencyclidine (PCP), an anesthetic and dissociative hallucinogen that acts primarily as an NMDA receptor antagonist.[1] The site is distinct from the PCP binding site on the NMDA receptor (otherwise known as PCP site 1) and the common/main sites on the monoamine transporters (SERT, DAT, NET).[1] It is associated with monoamine reuptake inhibition, and it has been suggested that the site may be an allosteric/regulatory site of the monoamine transporters.[1]

Phencyclidine, a high-affinity ligand of PCP site 2.

RTI-4793-14 (HBMP), a ligand with high affinity for the PCP site 2 and high selectivity for this site over the PCP site 1, has been developed.[2][3] Similarly to PCP, RTI-4793-1 inhibits monoamine reuptake with moderate potency, but unlike PCP, has very low potency as an NMDA receptor antagonist.[2] It shows a profile of a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI).[2] Although this was inferred to be related to binding to the PCP site 2, subsequent research found that RTI-4793-14 also has considerable affinity for the DAT; it does not appear to have been characterized at the SERT or NET, but may bind to them similarly, and these interactions could potentially explain its monoamine reuptake inhibition as an alternative to the PCP site 2.[3]

Activity profiles
Selected ligands, PCP sites, monoamine reuptake, and NMDAR inhibition[1]
CompoundRTI-4793-14Phencyclidine(+)-MK801Indatraline
PCP site 237.992.4>100002529
PCP site 1 (NMDAR)>360001174.58>20000
[3H]5-HT uptake10241424>47004.49
[3H]DA uptake547347>100003.23
[3H]CFT binding8501547>150004.32
[3H]Nisoxetine binding6091662865762.27
NMDA-induced current76820.02095
All values are IC50 (nM), except NMDA-induced current, which is IC50 (μM).
Ligand-selectivity in human brain[1]
CompoundPCP site 1
(Ki, nM)		PCP site 2
(Ki, nM)		Site 1 /
Site 2
(+)-MK-8018.9113670.00078
Tenocyclidine19.81970.10
Phencyclidine43.81540.28
Dexoxadrol9212340.075
Tiletamine93170500.0055
Ketamine831593880.014
Vanoxerine3092568414.5
BTCP46436210222.1
Benztropine78179233833.4
Bupropion101239375192.7
Fluoxetine106402167763.4
(–)-Cocaine267394230550.063
Ligand-selectivity in guinea pig brain[1]
CompoundPCP site 1
(Ki, nM)		PCP site 2
(Ki, nM)		Site 1 /
Site 2
Pargyline>10000003643>274
D-Amphetamine8050195941.1
Clomipramine63437468413.5
(–)-Cocaine282362601446.9
(+)-Cocaine>10000006383>157
Fluoxetine264590929285
Mazindol218993919238
Vanoxerine102118316732
Benztropine156890183857
Xylamine>1000000679>1473
Desipramine1195421375.6
Nomifensine139456260454
Bupropion>1000000704>1420
BTCP>10000001083>923
Ketamine81347020.17
Tiletamine79.313940.057
JMIII41C7092980.0075
JMII79B12.7185570.00068
PCA126213271.05
PPA646332002.0
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References
  1. Rothman RB (1994). "PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site" (PDF). Neurotoxicol Teratol. 16 (4): 343–53. doi:10.1016/0892-0362(94)90022-1. PMID 7968938.
  2. Goodman CB, Thomas DN, Pert A, Emilien B, Cadet JL, Carroll FI, Blough BE, Mascarella SW, Rogawski MA, Subramaniam S (1994). "RTI-4793-14, a new ligand with high affinity and selectivity for the (+)-MK801-insensitive [3H]1-]1-(2-thienyl)cyclohexyl]piperidine binding site (PCP site 2) of guinea pig brain". Synapse. 16 (1): 59–65. doi:10.1002/syn.890160107. PMID 8134901.
  3. Rothman RB, Silverthorn ML, Baumann MH, Goodman CB, Cadet JL, Matecka D, Rice KC, Carroll FI, Wang JB, Uhl GR (1995). "Studies of the biogenic amine transporters. VI. Characterization of a novel cocaine binding site, identified with [125I]RTI-55, in membranes prepared from whole rat brain minus caudate". J. Pharmacol. Exp. Ther. 274 (1): 385–95. PMID 7616423.


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