PNU-99,194

PNU-99,194(A) (or U-99,194(A)) is a drug which acts as a moderately selective D₃ receptor antagonist with ~15-30-fold preference for D₃ over the D₂ subtype.^[1][2][3] Though it has substantially greater preference for D₃ over D₂, the latter receptor does still play some role in its effects, as evidenced by the fact that PNU-99,194 weakly stimulates both prolactin secretion and striatal dopamine synthesis, actions it does not share with the more selective (100-fold) D₃ receptor antagonists S-14,297 and GR-103,691.^[4]

PNU-99,194

Clinical data
Routes of administration	Oral
ATC code	none
Legal status
Legal status	In general: uncontrolled
Identifiers
IUPAC name 5,6-dimethoxy-N,N-dipropyl-2,3-dihydro-1H-inden-2-amine
CAS Number	82668-33-5 83598-46-3 (maleate) 153570-58-2 (hydrochloride)
PubChem CID	5626
ChemSpider	5424
UNII	929J96FO8T
ChEMBL	ChEMBL16410
CompTox Dashboard (EPA)	DTXSID50274471
Chemical and physical data
Formula	C17H27NO2
Molar mass	277.408 g·mol−1
3D model (JSmol)	Interactive image
SMILES O(c1cc2c(cc1OC)CC(N(CCC)CCC)C2)C

In rodent studies, low doses of PNU-99,194 produce conditioned place preference (CPP) with no effect on intracranial self-stimulation (ICSS), whereas low doses of D₃ agonists like 7-OH-DPAT inhibit ICSS behavior and cause conditioned place aversion (CPA).^[5][6][7] In contrast, high doses of PNU-99,194 produce CPA and inhibit ICSS, while high doses of 7-OH-DPAT result in the opposite.^[5][6][7] Paralleling this, low doses of PNU-99,194 and 7-OH-DPAT induce hyperactivity and hypoactivity, respectively, whereas the inverse is seen at high doses with both agents.^{[2][3][7][8][9][10]} These data indicate that the D₃ receptor has biphasic effects on reward mechanisms and locomotor activity, likely due to opposing roles of autoreceptors versus postsynaptic receptors.^[8][11]

Other effects of PNU-99,194 at low doses in rodents include increased nociceptive responses,^[12] hypothermia,^[4][13] anxiolysis,^[14] and facilitation of learning and memory,^{[12][15][16][17]} as well as augmentation and inhibition, respectively, of amphetamine-induced reward and behavioral sensitization,^[18][19] and reversal of morphine-induced CPP.^[6] At high doses it inhibits the self-administration of cocaine in both rats and monkeys.^[1][20]

See also

• Nafadotride
• GSK-598809
• SB-277,011-A
• 7-OH-DPAT
• UH-232
• RDS-127

References

1. Claytor R, Lile JA, Nader MA (March 2006). "The effects of eticlopride and the selective D3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys". Pharmacology Biochemistry and Behavior. 83 (3): 456–64. doi:10.1016/j.pbb.2006.03.007. PMID 16631246. S2CID 39482275.
2. Waters N, Svensson K, Haadsma-Svensson SR, Smith MW, Carlsson A (1993). "The dopamine D3-receptor: a postsynaptic receptor inhibitory on rat locomotor activity". Journal of Neural Transmission. General Section. 94 (1): 11–9. doi:10.1007/bf01244979. PMID 8129881. S2CID 32918280.
3. Kling-Petersen T, Ljung E, Svensson K (1995). "Effects on locomotor activity after local application of D3 preferring compounds in discrete areas of the rat brain". Journal of Neural Transmission. General Section. 102 (3): 209–20. doi:10.1007/bf01281155. PMID 8788069. S2CID 10327706.
4. Audinot V, Newman-Tancredi A, Gobert A, et al. (October 1998). "A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194". The Journal of Pharmacology and Experimental Therapeutics. 287 (1): 187–97. PMID 9765337.
5. Kling-Petersen T, Ljung E, Wollter L, Svensson K (1995). "Effects of dopamine D3 preferring compounds on conditioned place preference and intracranial self-stimulation in the rat". Journal of Neural Transmission. General Section. 101 (1–3): 27–39. doi:10.1007/bf01271543. PMID 8695055. S2CID 30848393.
6. Francès H, Smirnova M, Leriche L, Sokoloff P (September 2004). "Dopamine D3 receptor ligands modulate the acquisition of morphine-conditioned place preference". Psychopharmacology. 175 (2): 127–33. doi:10.1007/s00213-004-1807-9. PMID 15095031. S2CID 2721240.
7. Khroyan TV, Baker DA, Neisewander JL (December 1995). "Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning". Psychopharmacology. 122 (4): 351–7. doi:10.1007/BF02246265. PMID 8657832. S2CID 20542615.
8. Millan MJ, Seguin L, Gobert A, Cussac D, Brocco M (July 2004). "The role of dopamine D3 compared with D2 receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel, selective antagonists in rats". Psychopharmacology. 174 (3): 341–57. doi:10.1007/s00213-003-1770-x. PMID 14985929. S2CID 1592299.
9. Gyertyán I, Sághy K (July 2004). "Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011". Behavioural Pharmacology. 15 (4): 253–62. doi:10.1097/01.fbp.0000137857.26150.ab. PMID 15252275. S2CID 41821358.
10. Rodríguez-Arias M, Felip CM, Broseta I, Miñarro J (May 1999). "The dopamine D3 antagonist U-99194A maleate increases social behaviors of isolation-induced aggressive male mice". Psychopharmacology. 144 (1): 90–4. doi:10.1007/s002130050981. PMID 10379629. S2CID 20953625. Archived from the original on 2000-07-12. Retrieved 2010-04-30.
11. Meyer ME (October 1996). "Mesolimbic 7-OH-DPAT affects locomotor activities in rats". Pharmacology Biochemistry and Behavior. 55 (2): 209–14. doi:10.1016/S0091-3057(96)00066-4. PMID 8951956. S2CID 46728735.
12. Casarrubea M, Sorbera F, Crescimanno G (November 2006). "Effects of 7-OH-DPAT and U 99194 on the behavioral response to hot plate test, in rats". Physiology & Behavior. 89 (4): 552–62. doi:10.1016/j.physbeh.2006.07.014. PMID 16919688. S2CID 45464906.
13. Boulay D, Depoortere R, Rostene W, Perrault G, Sanger DJ (April 1999). "Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice". Neuropharmacology. 38 (4): 555–65. doi:10.1016/S0028-3908(98)00213-5. PMID 10221759. S2CID 1004412.
14. Rogóz Z, Kłodzińska A, Maj J (2000). "Anxiolytic-like effect of nafadotride and PNU 99194A, dopamine D3 receptor antagonists in animal models". Polish Journal of Pharmacology. 52 (6): 459–62. PMID 11334239.
15. Laszy J, Laszlovszky I, Gyertyán I (May 2005). "Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats". Psychopharmacology. 179 (3): 567–75. doi:10.1007/s00213-004-2096-z. PMID 15619116. S2CID 24086632.
16. Hale MW, Crowe SF (July 2002). "The effects of selective dopamine agonists on a passive avoidance learning task in the day-old chick". Behavioural Pharmacology. 13 (4): 295–301. doi:10.1097/00008877-200207000-00006. PMID 12218510. S2CID 24698131.
17. Hammad H, Wagner JJ (January 2006). "Dopamine-mediated disinhibition in the CA1 region of rat hippocampus via D3 receptor activation". The Journal of Pharmacology and Experimental Therapeutics. 316 (1): 113–20. doi:10.1124/jpet.105.091579. PMID 16162819. S2CID 10007327.
18. Carr KD, Yamamoto N, Omura M, Cabeza de Vaca S, Krahne L (August 2002). "Effects of the D(3) dopamine receptor antagonist, U99194A, on brain stimulation and d-amphetamine reward, motor activity, and c-fos expression in ad libitum fed and food-restricted rats". Psychopharmacology. 163 (1): 76–84. doi:10.1007/s00213-002-1132-0. PMID 12185403. S2CID 1840764.
19. Chiang YC, Chen PC, Chen JC (May 2003). "D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine". Brain Research. 972 (1–2): 159–67. doi:10.1016/S0006-8993(03)02522-8. PMID 12711089. S2CID 40067321.
20. Gál K, Gyertyán I (October 2003). "Targeting the dopamine D3 receptor cannot influence continuous reinforcement cocaine self-administration in rats". Brain Research Bulletin. 61 (6): 595–601. doi:10.1016/S0361-9230(03)00217-X. PMID 14519456. S2CID 12383682.