Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics

Saitton, Stina, 1972 (author): Umeå universitet,Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry,Kemiska institutionen,Göteborg University, Department of Chemistry, Medicinal Chemistry, SE- 412 96, Göteborg, Sweden

Del Tredici, Andria L (author)

Saxin, Maria, 1979 (author): Umeå universitet,Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry,Kemiska institutionen,Göteborg University, Department of Chemistry, Medicinal Chemistry, SE- 412 96, Göteborg, Sweden

Luthman, Kristina, 1953 (author): Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry

(creator_code:org_t)

Royal Society of Chemistry (RSC), 2008
2008
English.
In: Org. Biomol. Chem.. - : Royal Society of Chemistry (RSC). ; 6, s. 1647-1654

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.1...; https://urn.kb.se/re...; show less...

Abstract Subject headings

Analogues of the pyridine based PLG (Pro-Leu-Gly-NH2) peptidomimetic 1 were synthesized and evaluated as dopamine modulating agents. Modifications in the position corresponding to the leucine side chain in PLG afforded derivatives 2, 3 and 4, substituted with H, Me and Bn instead of the isobutyl group, respectively. Changes in the proline residue produced derivative 5, substituted with a symmetrical piperidine ring instead of the pyrrolidine ring and 6, in which the pyrrolidine ring is connected to the pyridine ring via a hydroxymethyl group instead of a keto function. The peptidomimetics were tested for their ability to enhance the maximal effect of N-propylapomorphine (NPA) at dopamine D2 receptors in the functional cell-based R-SAT assay. Compounds 2, 3, and 4, produced a statistically significant increase in the maximal NPA response at 10 nM (117 ± 6%, 118 ± 6%, and 116 ± 3%, respectively), which is similar to the effect of PLG in this assay, whereas 5 was able to potentiate the response to a similar extent at 1 nM concentration (115 ± 5%). All derivatives produced a bell-shaped dose–response curve and none of the compounds were active at the D2 receptor alone, which indicates that the mechanism behind the activity of both the pyridine based mimetics 1–6 and PLG is the same. Interestingly, L-Pro-D-Leu-Gly-NH2 was found to be more potent than PLG and produced a 119 ± 1% increase in the NPA response at 1 nM.

By the author/editor: Saitton, Stina, ...; Del Tredici, And ...; Saxin, Maria, 19 ...; Stenström, Tobia ...; Kihlberg, Jan; Luthman, Kristin ...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Organic Chemistr ...

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