Linked Life Data

10691681

Source:http://linkedlifedata.com/resource/pubmed/id/10691681

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2000-3-16
pubmed:abstractText
Recently we reported using minilibraries to replace Lys(9) [somatostatin (SRIF) numbering] of the potent somatostatin agonist L-363,301 (c[-Pro-Phe-D-Trp-Lys-Thr-Phe-]) to generate the potent neurokinin receptor (NK-1) antagonist c[-Pro-Phe-D-Trp-p-F-Phe-Thr-Phe-]. This novel cyclic hexapeptide did not bind the SRIF receptor. Thus, a single mutation converted L-363,301, a SRIF agonist with potency ca. 2-8 times the potency of SRIF in laboratory animals,(24) into a selective NK-1 receptor antagonist with an IC(50) of 2 nM in vitro. During the screening of the same libraries for ligands of the delta-opioid receptor, we identified four compounds (1-4) which represent a new class of delta-opioid antagonists, some of which were also NK-1 receptor antagonists. The most potent delta-opioid antagonist, c[-Pro-1-Nal-D-Trp-Tyr-Thr-Phe-] (2), showed a K(e) value of 128 nM in the mouse vas deferens assay and a delta-receptor binding affinity constant of 152 nM in the rat brain membrane binding assay. These results are of interest because they represent a novel class of delta-opioid antagonists and, like two previously reported delta-opioid antagonists, they lack a positive charge. To examine further the requirement for a positive charge in the delta-opioid ligands, we prepared two analogues of the beta-casomorphin-derived mixed mu-agonist/delta-antagonist, H-Dmt-c[-D-Orn-2-Nal-D-Pro-Gly-] (7), in which we eliminated the positive charge either through formylation of the primary amino group (5) or by the deletion of this N-terminal amino group (6). These latter compounds proved to be delta-opioid antagonists with K(e) values in the 16-120 nM range, as well as fairly potent mu-opioid antagonists (K(e) approximately 200 nM). These six compounds provide the most convincing evidence to date that there is no requirement for a positive charge in mu- and delta-opioid receptor antagonists. In addition, cyclic hexapeptide 4 lacks a phenolic hydroxyl group. Taken together, these data suggest that the prevailing assumptions about delta- and mu-opioid receptor binding need revision and that the receptors for these opioid ligands have much in common with the NK-1 and somatostatin receptors.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
551-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10691681-Animals, pubmed-meshheading:10691681-Binding, Competitive, pubmed-meshheading:10691681-Brain, pubmed-meshheading:10691681-Guinea Pigs, pubmed-meshheading:10691681-Ileum, pubmed-meshheading:10691681-Ligands, pubmed-meshheading:10691681-Male, pubmed-meshheading:10691681-Mice, pubmed-meshheading:10691681-Muscle, Smooth, pubmed-meshheading:10691681-Muscle Contraction, pubmed-meshheading:10691681-Narcotic Antagonists, pubmed-meshheading:10691681-Oligopeptides, pubmed-meshheading:10691681-Peptides, Cyclic, pubmed-meshheading:10691681-Radioligand Assay, pubmed-meshheading:10691681-Rats, pubmed-meshheading:10691681-Receptors, Neurokinin-1, pubmed-meshheading:10691681-Receptors, Opioid, mu, pubmed-meshheading:10691681-Structure-Activity Relationship, pubmed-meshheading:10691681-Vas Deferens
pubmed:year
2000
pubmed:articleTitle
Novel ligands lacking a positive charge for the delta- and mu-opioid receptors.
pubmed:affiliation
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, 110 Pine Avenue West, Montréal, Quebec, Canada.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't