期刊
CHEMICAL & PHARMACEUTICAL BULLETIN
卷 60, 期 8, 页码 945-948出版社
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/cpb.c12-00336
关键词
opioid; kappa receptor; decahydroisoquinoline; nalfurafine; three-dimensional pharmacophore model
资金
- Shorai Foundation for Science
- Uehara Memorial Foundation
- JSPS KAKENHI [23590133]
- Grants-in-Aid for Scientific Research [23590133, 22590042] Funding Source: KAKEN
On the basis of the three-dimensional pharmacophore model of opioid kappa agonists, we simplified the structure of nalfurafine (selective kappa agonist) to find the essential structural moieties for binding the opioid receptors, especially kappa receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the kappa selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives. These findings that the simple decahydroisoquinoline derivatives showed the affinities for the opioid receptors, especially some of the compounds showed kappa selectivity, are the first example in the opioid field.
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