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1.
Org Lett ; 3(5): 695-8, 2001 Mar 08.
Article in English | MEDLINE | ID: mdl-11259039

ABSTRACT

[structure: see text]. The solution structure of (+)-discodermolide (1) has been determined via 1- and 2-D NMR techniques in conjunction with Monte Carlo conformational analysis. Taken together, the results demonstrate that in solution (+)-discodermolide occupies a helical conformation remarkably similar to the solid state conformation.


Subject(s)
Alkanes , Carbamates , Immunosuppressive Agents/chemistry , Lactones/chemistry , Porifera/chemistry , Animals , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Monte Carlo Method , Pyrones , Solutions , Tubulin/chemistry
2.
J Med Chem ; 43(4): 551-9, 2000 Feb 24.
Article in English | MEDLINE | ID: mdl-10691681

ABSTRACT

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.


Subject(s)
Narcotic Antagonists/chemical synthesis , Oligopeptides/chemical synthesis , Peptides, Cyclic/chemical synthesis , Receptors, Opioid, mu/antagonists & inhibitors , Animals , Binding, Competitive , Brain/metabolism , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Ligands , Male , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Narcotic Antagonists/chemistry , Narcotic Antagonists/pharmacology , Neurokinin-1 Receptor Antagonists , Oligopeptides/chemistry , Oligopeptides/metabolism , Oligopeptides/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacology , Radioligand Assay , Rats , Receptors, Neurokinin-1/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship , Vas Deferens/drug effects
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