DPAI

Last updated
DPAI
DPAI structure.svg
Clinical data
Other names4-(N,N-Dipropylaminoethyl)indole; 4-DPAEI; 2-Desoxo-2-ene-ropinirole
Drug class Dopamine receptor agonist; Prolactin inhibitor
ATC code
  • None
Identifiers
  • N-[2-(1H-indol-4-yl)ethyl]-N-propylpropan-1-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H24N2
Molar mass 244.382 g·mol−1
3D model (JSmol)
  • CCCN(CCC)CCC1=C2C=CNC2=CC=C1
  • InChI=1S/C16H24N2/c1-3-11-18(12-4-2)13-9-14-6-5-7-16-15(14)8-10-17-16/h5-8,10,17H,3-4,9,11-13H2,1-2H3
  • Key:AFRBPRLOPBAGCM-UHFFFAOYSA-N

DPAI, also known as 4-(N,N-dipropylaminoethyl)indole (4-DPAEI) or as 2-desoxo-2-ene-ropinirole, is a dopamine receptor agonist and partial ergoline closely related to the clinically used dopamine receptor agonist and antiparkinsonian agent ropinirole. [1] [2] [3]

Contents

It has a delayed onset of effects and weak actions in vitro , suggestive that it may be a metabolically activated prodrug via 6-hydroxylation into its metabolite 6-HO-DPAI (TL-350). [4] [2] [3] [5] The drug is said to be a highly selective agonist of presynaptic dopamine autoreceptors, with little or no activity at postsynaptic dopamine receptors. [1] [6] [7] [8] It dramatically reduces dopamine release in the caudate nucleus, produces hypolocomotion, and strongly suppresses prolactin secretion in rodents. [1] [7] [8] [9] [10]

DPAI was first described in the scientific literature by 1980. [3] [1] It was developed independently by David E. Nichols and colleagues and by another group of researchers. [10]

See also

References

  1. 1 2 3 4 Clemens, J. A., Kornfeld, E. C., Phebus, L. A., Shaar, C. J., Smalstig, E. B., Cassady, J. M., ... & Kelly, E. (1982). Dopaminergic Agents Related to Ergolines. In The Chemical Regulation of Biological Mechanisms: The Proceedings of the 1st Medicinal Chemistry Symposium, Cambridge, England, 27th-30 September 1981 (Vol. 42, p. 167). London: Royal Society of Chemistry. https://archive.org/details/chemicalregulati0000medi/page/167/mode/1up
  2. 1 2 David E. Nichols (29 June 1983). "The Development of Novel Dopamine Agonists". Dopamine Receptors. ACS Symposium Series. Vol. 224. Washington, D.C.: American Chemical Society. pp. 201–222. doi:10.1021/bk-1983-0224.ch009. ISBN   978-0-8412-0781-3. The situation seems further confounded by the reports (13) of dopaminergic activity for the 4-substituted aminoethylindole DPAI, IX. However, the delayed onset of action reported by Cannon et al . (13) for this compound, as well as a weak in vitro action (14), lead to the possibility that DPAI may be metabolically activated by hydroxylation at the 6-position. This is a common transformation for indoles. Indeed, lergotrile is hydroxylated at the corresponding 13 position to yield a metabolite which is an order of magnitude more potent than lergotrile itself (15).
  3. 1 2 3 Bach NJ, Kornfeld EC, Jones ND, Chaney MO, Dorman DE, Paschal JW, Clemens JA, Smalstig EB (May 1980). "Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl)pyrroles and 3- and 4-(2-aminoethyl)pyrazoles as dopamine agonists". J Med Chem. 23 (5): 481–491. doi:10.1021/jm00179a003. PMID   7189782.
  4. ↑ Wikström H, Lii JH, Allinger NL (October 1987). "The dopaminergic moiety of the ergots: a controversial topic studied with molecular mechanics". J Med Chem. 30 (10): 1928–1934. doi:10.1021/jm00393a041. PMID   3656365. In the first publication on DPAI it was implied that this compound might have to be bioactivated before excerting its effect.10 Consequently, the same authors later showed that 6-OH-DPAI (10) really is more active than DPAI itself, and in addition, it is active in vitro and has no lag period before excerting its effect in vivo, which is the case with DPAI.21 This very interesting finding is fully in concert with the previously discussed metabolic activation, i.e., the 13-hydroxylation of the ergots.
  5. ↑ Cannon JG, Lee T, Ilhan M, Koons J, Long JP (March 1984). "6-Hydroxy-4-[2-(di-n-propylamino)ethyl]indole: synthesis and dopaminergic actions". J Med Chem. 27 (3): 386–389. doi:10.1021/jm00369a026. PMID   6699883.
  6. ↑ Clark D, Hjorth S, Carlsson A (1985). "Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of the evidence". J Neural Transm. 62 (1–2): 1–52. doi:10.1007/BF01260414. PMID   3894582. Also of considerable interest are those agonists which have been suggested to act selectively at DA autoreceptors. These include racemic 3-PPP (Hjorth et al., 1980, 1981), DPAI (Clemens et al., 1984), EMD 23448 (Chiodo and Bunney, 1983) and B-HT 920 (Anden et al, 1983 a, b, c), [...]
  7. 1 2 Clark D, Hjorth S, Carlsson A (1985). "Dopamine receptor agonists: mechanisms underlying autoreceptor selectivity. II. Theoretical considerations". J Neural Transm. 62 (3–4): 171–207. doi:10.1007/BF01252236. PMID   2863323. This suggestion was in part based on work with various DA antagonists considered to possess differential blocking capacity at DA autoreceptors vs. postsynaptic receptors. In further support of this interpretation, TDHL (Wachtd and Dorow, 1983), DPAI (Clemens et al., 1984) and B-HT 920 (And~n et al., 1983 a, b) all lack intrinsic activity at normosensitive postsynaptic DA receptors but strongly reduce serum prolactin levels (Clemens et aL, 1984; Wachtel and Dorow, 1983; Eriksson et al., 1985).
  8. 1 2 Clemens JA, Fuller RW, Phebus LA, Smalstig EB, Hynes MD, Cassady JM, Nichols DE, Kelly E, Persons P (March 1984). "Stimulation of presynaptic dopamine autoreceptors by 4-(2-di-n-propylaminoethyl) indole (DPAI)". Life Sci. 34 (11): 1015–1022. doi:10.1016/0024-3205(84)90014-6. PMID   6422174.
  9. ↑ Nichols DE, Cassady JM, Persons PE, Yeung MC, Clemens JA, Smalstig EB (September 1989). "Synthesis and evaluation of N,N-di-n-propyltetrahydrobenz[f]indol-7-amine and related congeners as dopaminergic agonists". J Med Chem. 32 (9): 2128–2134. doi:10.1021/jm00129a017. PMID   2570151.
  10. 1 2 Persons, PE; Mayer, JP; Nichols, DE; Cassady, JM; Smalstig, EB; Clemens, JA (1991). "Preliminary evaluation of 4-(2-N,N-dialkylaminoethyl)indoles as potential dopamine agonists". European Journal of Medicinal Chemistry. 26 (4). Elsevier BV: 473–475. doi:10.1016/0223-5234(91)90110-9. ISSN   0223-5234.
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