PCP site 2

Phencyclidine, a high-affinity ligand of 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 (SERTTooltip serotonin transporter, DATTooltip dopamine transporter, NETTooltip norepinephrine transporter).[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]

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]
Compound RTI-4793-14 Phencyclidine (+)-MK801 Indatraline
PCP site 2 37.9 92.4 >10000 2529
PCP site 1 (NMDAR) >36000 117 4.58 >20000
[3H]5-HT uptake 1024 1424 >4700 4.49
[3H]DA uptake 547 347 >10000 3.23
[3H]CFT binding 850 1547 >15000 4.32
[3H]Nisoxetine binding 609 16628 6576 2.27
NMDA-induced current 768 2 0.020 95
All values are IC50 (nM), except NMDA-induced current, which is IC50 (μM).
Ligand-selectivity in human brain[1]
Compound PCP site 1
(Ki, nM)		 PCP site 2
(Ki, nM)		 Site 1 /
Site 2
(+)-MK-801 8.9 11367 0.00078
Tenocyclidine 19.8 197 0.10
Phencyclidine 43.8 154 0.28
Dexoxadrol 92 1234 0.075
Tiletamine 93 17050 0.0055
Ketamine 831 59388 0.014
Vanoxerine 30925 6841 4.5
BTCP 46436 2102 22.1
Benztropine 78179 2338 33.4
Bupropion 101239 37519 2.7
Fluoxetine 106402 1677 63.4
(–)-Cocaine 26739 423055 0.063
Ligand-selectivity in guinea pig brain[1]
Compound PCP site 1
(Ki, nM)		 PCP site 2
(Ki, nM)		 Site 1 /
Site 2
Pargyline >1000000 3643 >274
D-Amphetamine 80501 959 41.1
Clomipramine 63437 4684 13.5
(–)-Cocaine 282362 6014 46.9
(+)-Cocaine >1000000 6383 >157
Fluoxetine 264590 929 285
Mazindol 218993 919 238
Vanoxerine 102118 3167 32
Benztropine 156890 183 857
Xylamine >1000000 679 >1473
Desipramine 11954 2137 5.6
Nomifensine 139456 2604 54
Bupropion >1000000 704 >1420
BTCP >1000000 1083 >923
Ketamine 813 4702 0.17
Tiletamine 79.3 1394 0.057
JMIII41C 70 9298 0.0075
JMII79B 12.7 18557 0.00068
PCA 1262 1327 1.05
PPA 6463 3200 2.0

References

  1. ^ a b c d e f Rothman RB (1994). "PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site". Neurotoxicol Teratol. 16 (4): 343–53. doi:10.1016/0892-0362(94)90022-1. PMID 7968938.
  2. ^ a b c 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. S2CID 19829696.
  3. ^ a b 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.