PNU-99,194

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PNU-99,194
PNU-99194A-structure.png
Systematic (IUPAC) name
5,6-dimethoxy-N,N-dipropyl-2,3-dihydro-1H-inden-2-amine
Clinical data
  • Uncontrolled
Oral
Identifiers
82668-33-5
83598-46-3 (maleate)
153570-58-2 (hydrochloride)
None
PubChem CID 5626
ChemSpider 5424
ChEMBL CHEMBL16410
Chemical data
Formula C17H27NO2
277.40 g/mol

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]

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[edit]

References[edit]

  1. ^ a b 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. 
  2. ^ a b 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. 
  3. ^ a b 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. 
  4. ^ a b 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. ^ a b 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. 
  6. ^ a b c 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. 
  7. ^ a b c 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. 
  8. ^ a b 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. 
  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. 
  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. 
  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. 
  12. ^ a b 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. 
  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. 
  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. 
  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. 
  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. 
  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. 
  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. 
  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.