Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
|
| pubmed:dateCreated |
1992-6-9
|
| pubmed:abstractText |
A Free-Wilson/Fujita-Ban (FW/FB) analysis is reported on 36 "dipeptoid" antagonists of the CCK-B receptor. This series of compounds includes [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1] dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]- 4-oxobutanoic acid (CI-988, 1, Figure 1), the first rationally designed non-peptide antagonist of a neuropeptide receptor. The analysis treats the compounds in three parts: the N-terminus, variants on the tryptophan moiety, and the C-terminus. A highly significant correlation was found (n = 36, r2 = 0.97, s = 0.22, F = 57, p = 2 x 10(-8)), suggesting that these three domains of these compounds contribute to binding affinity independently of each other, and are therefore additive in their effects on receptor affinity. The relative free-energies of binding of the individual substituents are calculated from the coefficients of the regression equation. The substitution of D-alpha-methyltryptophan for L-tryptophan increases the free-energy of binding by 3.5 kcal mol-1. This increase in binding energy is explained by a 300-fold difference in conformational entropy between the methylated and desmethyl analogues.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
35
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1572-7
|
| pubmed:dateRevised |
2003-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:1578483-Animals,
pubmed-meshheading:1578483-Cerebral Cortex,
pubmed-meshheading:1578483-Cholecystokinin,
pubmed-meshheading:1578483-Drug Design,
pubmed-meshheading:1578483-Male,
pubmed-meshheading:1578483-Mice,
pubmed-meshheading:1578483-Models, Molecular,
pubmed-meshheading:1578483-Receptors, Cholecystokinin,
pubmed-meshheading:1578483-Thermodynamics,
pubmed-meshheading:1578483-Tryptophan
|
| pubmed:year |
1992
|
| pubmed:articleTitle |
Rationally designed "dipeptoid" analogues of CCK. A Free-Wilson/Fujita-Ban analysis of some alpha-methyltryptophan derivatives as CCK-B antagonists.
|
| pubmed:affiliation |
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital, Cambridge, U.K.
|
| pubmed:publicationType |
Journal Article
|