SB-277,011-A

SB-277,011A is a drug which acts as a potent and selective dopamine D3 receptor antagonist,[1] which is around 80-100x selective for D3 over D2,[2] and lacks any partial agonist activity.[3]

SB-277,011-A
Identifiers
IUPAC name
  • N-{trans-4-[2-(6-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]cyclohexyl}quinoline-4-carboxamide
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC28H30N4O
Molar mass438.575 g·mol−1
3D model (JSmol)
SMILES
  • c4cccc1c4nccc1C(=O)NC3CCC(CC3)CCN(CCc2c5)Cc2ccc5C#N
InChI
  • InChI=1S/C28H30N4O/c29-18-21-5-8-23-19-32(16-13-22(23)17-21)15-12-20-6-9-24(10-7-20)31-28(33)26-11-14-30-27-4-2-1-3-25(26)27/h1-5,8,11,14,17,20,24H,6-7,9-10,12-13,15-16,19H2,(H,31,33) N
  • Key:OLWRVVHPJFLNPW-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

SB-277,011A is used in the study of addiction to stimulant drugs such as nicotine[4] and cocaine.[5][6] Where cocaine reduces the threshold for brain electrical self-stimulation in rats, an indication of cocaine's rewarding effects, SB-277,011A completely reverses this effect. It may thus be useful in the treatment of addiction to nicotine and cocaine,[7][8][9] and is also being investigated for potential uses in the treatment of other drug addictions, such as addiction to heroin[10] and alcohol.[11][12][13]

Another potential application for SB-277,011A is in the treatment of schizophrenia,[14] and it may be particularly useful in treating comorbid patients who are both schizophrenic and addicted to drugs.[15] However it may worsen side effects such as tardive dyskinesia in patients who are already prescribed antipsychotic drugs.[16]

References

  1. Stemp G, Ashmeade T, Branch CL, Hadley MS, Hunter AJ, Johnson CN, et al. (May 2000). "Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat". Journal of Medicinal Chemistry. 43 (9): 1878–85. doi:10.1021/jm000090i. PMID 10794704.
  2. Southam E, Lloyd A, Jennings CA, Cluderay JE, Cilia J, Gartlon JE, Jones DN (May 2007). "Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain". Brain Research. 1149: 50–7. doi:10.1016/j.brainres.2007.02.051. PMID 17382304. S2CID 12557234.
  3. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, et al. (September 2000). "Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A". The Journal of Pharmacology and Experimental Therapeutics. 294 (3): 1154–65. PMID 10945872.
  4. Le Foll B, Schwartz JC, Sokoloff P (February 2003). "Disruption of nicotine conditioning by dopamine D(3) receptor ligands". Molecular Psychiatry. 8 (2): 225–30. doi:10.1038/sj.mp.4001202. PMID 12610655.
  5. Vorel SR, Ashby CR, Paul M, Liu X, Hayes R, Hagan JJ, et al. (November 2002). "Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats". The Journal of Neuroscience. 22 (21): 9595–603. doi:10.1523/JNEUROSCI.22-21-09595.2002. PMC 6758043. PMID 12417684.
  6. Di Ciano P, Underwood RJ, Hagan JJ, Everitt BJ (February 2003). "Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A". Neuropsychopharmacology. 28 (2): 329–38. doi:10.1038/sj.npp.1300148. PMID 12589386.
  7. Andreoli M, Tessari M, Pilla M, Valerio E, Hagan JJ, Heidbreder CA (July 2003). "Selective antagonism at dopamine D3 receptors prevents nicotine-triggered relapse to nicotine-seeking behavior". Neuropsychopharmacology. 28 (7): 1272–80. doi:10.1038/sj.npp.1300183. PMID 12700694.
  8. Ross JT, Corrigall WA, Heidbreder CA, LeSage MG (March 2007). "Effects of the selective dopamine D3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats". European Journal of Pharmacology. 559 (2–3): 173–9. doi:10.1016/j.ejphar.2007.01.004. PMID 17303116.
  9. Xi ZX, Gilbert J, Campos AC, Kline N, Ashby CR, Hagan JJ, et al. (October 2004). "Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats". Psychopharmacology. 176 (1): 57–65. doi:10.1007/s00213-004-1858-y. PMC 3726040. PMID 15083257.
  10. Ashby CR, Paul M, Gardner EL, Heidbreder CA, Hagan JJ (June 2003). "Acute administration of the selective D3 receptor antagonist SB-277011A blocks the acquisition and expression of the conditioned place preference response to heroin in male rats". Synapse. 48 (3): 154–6. doi:10.1002/syn.10188. PMID 12645041. S2CID 26458149.
  11. Thanos PK, Katana JM, Ashby CR, Michaelides M, Gardner EL, Heidbreder CA, Volkow ND (May 2005). "The selective dopamine D3 receptor antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats". Pharmacology, Biochemistry, and Behavior. 81 (1): 190–7. doi:10.1016/j.pbb.2005.03.013. PMID 15894078. S2CID 15406751.
  12. Vengeliene V, Leonardi-Essmann F, Perreau-Lenz S, Gebicke-Haerter P, Drescher K, Gross G, Spanagel R (November 2006). "The dopamine D3 receptor plays an essential role in alcohol-seeking and relapse". FASEB Journal. 20 (13): 2223–33. doi:10.1096/fj.06-6110com. PMID 17077299. S2CID 9431585.
  13. Heidbreder CA, Andreoli M, Marcon C, Hutcheson DM, Gardner EL, Ashby CR (March 2007). "Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice". Addiction Biology. 12 (1): 35–50. doi:10.1111/j.1369-1600.2007.00051.x. PMID 17407496. S2CID 25984106.
  14. Joyce JN, Millan MJ (July 2005). "Dopamine D3 receptor antagonists as therapeutic agents". Drug Discovery Today. 10 (13): 917–25. doi:10.1016/S1359-6446(05)03491-4. PMID 15993811.
  15. Jahnke U (January 2008). "Experimental pharmacotherapeutics for schizophrenia and addiction". IDrugs. 11 (1): 7–9. PMID 18175251.
  16. Malik P, Andersen MB, Peacock L (August 2004). "The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia". Pharmacology, Biochemistry, and Behavior. 78 (4): 805–10. doi:10.1016/j.pbb.2004.05.019. PMID 15301939. S2CID 19410897.
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