S32504

S32504
Clinical data
Other namesS-32504; S-32,504
Routes of
administration		Unspecified[1]
Drug classDopamine receptor agonist; Dopamine D2 and D3 receptor agonist
ATC code
  • None
Identifiers
  • (4aR,10bR)-4-propyl-2,3,4a,5,6,10b-hexahydrobenzo[h][1,4]benzoxazine-9-carboxamide
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC16H22N2O2
Molar mass274.364 g·mol−1
3D model (JSmol)
  • CCCN1CCO[C@H]2[C@H]1CCC3=C2C=C(C=C3)C(=O)N
  • InChI=1S/C16H22N2O2/c1-2-7-18-8-9-20-15-13-10-12(16(17)19)4-3-11(13)5-6-14(15)18/h3-4,10,14-15H,2,5-9H2,1H3,(H2,17,19)/t14-,15-/m1/s1
  • Key:XKTRZPQOQOCNJU-HUUCEWRRSA-N

S32504 is a dopamine D2 and D3 receptor agonist which was under development for the treatment of Parkinson's disease but was never marketed.[1][2][3] Its route of administration was unspecified.[1]

Pharmacology

Pharmacodynamics

S32504 acts as a potent and selective agonist of the dopamine D3 and D2 receptors, with EC50Tooltip half-maximal effective concentration values of 2.0–3.2 nM and 2.5–398 nM, respectively, depending on the assay.[3] It is a preferential agonist of the dopamine D3 receptor over the dopamine D2 receptor.[3] The drug showed little affinity for or activity at more than 50 other receptors and targets, including the dopamine D1, D4, and D5 receptors and the serotonin 5-HT1A and 5-HT2A receptors, among others.[3] S32504 suppressed the activity of dopaminergic neurons in the ventral tegmental area (VTA) in rodents.[3] In addition, it potently reduced levels of dopamine in the striatum, nucleus accumbens, and frontal cortex, which could be reversed by the dopamine D2 and D3 receptor antagonist haloperidol and by the selective dopamine D2 receptor antagonist L-741,626, but not by the selective dopamine D3 receptor antagonist S33084.[3]

The drug produces antiparkinsonian effects in rodents and monkeys and antidepressant- and anxiolytic-like effects in rodents.[4][5] The antiparkinsonian effects of S32504 could be blocked by the dopamine D2 and D3 receptor antagonists haloperidol and raclopride and by L-741,626, but not by S33084, suggesting mediation of these actions by the dopamine D2 receptor and not by the dopamine D3 receptor.[4] However, the dopamine D3 receptor appeared to be involved in dopaminergic neuroprotective effects of S32504.[4] The antidepressant- and anxiolytic-like effects of S32504 were blocked by haloperidol, raclopride, and L-741,626 but not by S33084, again suggesting involvement of the dopamine D2 receptor and not the dopamine D3 receptor in these effects.[5] In rats treated with the dopamine depleting agent reserpine and monkeys treated with the dopaminergic neurotoxin MPTP, S32504 reversed hypolocomotion.[4] Conversely, in untreated rodents, S32504 produced hypolocomotion over a wide range of doses and did not produce hyperlocomotion at any assessed dose.[5]

Chemistry

Analogues

Analogues of S32504 with enhanced affinity and selectivity for the dopamine D3 receptor over the dopamine D2 receptor have been developed and described.[6]

History

S32504 was first described in the scientific literature by 1999.[7][8]

Research

S32504 was being developed for the treatment of Parkinson's disease by Servier in France.[1][2] It reached the preclinical research stage of development prior to its development being discontinued.[1][2] No recent development was reported by 2003.[1]

See also

References

  1. ^ a b c d e f "S 32504". AdisInsight. 3 November 2003. Retrieved 31 January 2026.
  2. ^ a b c "Delving into the Latest Updates on S-32504 with Synapse". Synapse. 3 January 2026. Retrieved 31 January 2026.
  3. ^ a b c d e f Millan MJ, Cussac D, Gobert A, Lejeune F, Rivet JM, Mannoury La Cour C, et al. (June 2004). "S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: I. Cellular, electrophysiological, and neurochemical profile in comparison with ropinirole". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 903–920. doi:10.1124/jpet.103.062398. PMID 14978194.
  4. ^ a b c d Millan MJ, Di Cara B, Hill M, Jackson M, Joyce JN, Brotchie J, et al. (June 2004). "S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: II. Actions in rodent, primate, and cellular models of antiparkinsonian activity in comparison to ropinirole". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 921–935. doi:10.1124/jpet.103.062414. PMID 14978195.
  5. ^ a b c Millan MJ, Brocco M, Papp M, Serres F, La Rochelle CD, Sharp T, et al. (June 2004). "S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: III. Actions in models of potential antidepressive and anxiolytic activity in comparison with ropinirole". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 936–950. doi:10.1124/jpet.103.062463. PMID 14978196.
  6. ^ Peglion JL, Poitevin C, Mannoury La Cour C, Dupuis D, Millan MJ (April 2009). "Modulations of the amide function of the preferential dopamine D3 agonist (R,R)-S32504: improvements of affinity and selectivity for D3 versus D2 receptors". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2133–2138. doi:10.1016/j.bmcl.2009.03.015. PMID 19324548.
  7. ^ Millan, M. J., Brocco, M., Dekeyne, A., Newman-Tancredi, A., Cussac, D., Lejeune, F., ... & Peglion, J. L. (1999). S32504, a novel and potent naphtoxazine agonist at dopamine D3 receptors. In Soc. Neurosci. Abstr (Vol. 25, p. 1467). https://scholar.google.com/scholar?cluster=15404362878406761756
  8. ^ Peglion JL, Harmange JC, Cussac D, Millan MJ (August 2001). Discovery of S 32504 A preferential agonist at dopamine D3 vs. D2 receptors possessing antiparkinsonian and antidepressant properties. 222nd ACS National Meeting. Art. MEDI-208. Chicago, IL, United States: American Chemical Society.
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