Torrey Pines Institute for Molecular Studies

Trega Biosciences, Inc.

Houghten Pharmaceuticals, Inc.

Colette T Dooley

Richard Allen Houghten

John M Ostresh

Barbara Dorner

Jutta Eichler

The instant invention is directed to a single, selectively N-alkylated compound and libraries of such compounds as set forth in Formula I. Furthermore, the instant invention is directed to methods of effecting analgesia, a decrease in the postprandial rise in the blood glucose levels of a mammal after ingestion of a carbohydrate load by said mammal, and treating microbial infections, utilizing such a single compound of Formula I in conjunction with a pharmaceutically-acceptable carrier. Also, the instant invention is directed to methods for selective alkylation, positional scanning and iterative synthetic and screening technologies.

Selectively N-alkylated peptidomimetic combinatorial libraries and

The present invention provides novel opioid peptides. Disclosed are opioid peptides having the general structures Ac-Phe-Arg-Trp-Trp-Tyr-Xaa-NH.sub.2 (SEQ ID NO. 1); Ac-Arg-Trp-Ile-Gly-Trp-Xaa-NH.sub.2 (SEQ ID NO. 2); Trp-Trp-Pro-Lys-His-Xaa-NH.sub.2 (SEQ ID NO. 3); and shorter versions of the latter, namely, Trp-Trp-Pro-Xaa-NH.sub.2 (SEQ ID NO. 4); Tyr-Pro-Phe-Gly-Phe-Xaa-NH.sub.2 (SEQ ID NO. 5); (D)Ile-(D)Met-(D)Ser-(D)Trp-(D)Trp-Gly.sub.n -Xaa-NH.sub.2 (SEQ ID NO. 6); and (D)Ile-(D)Met-(D)Thr-(D)Trp-Gly-Xaa-NH.sub.2 (SEQ ID NO. 7). Within each genus, Xaa is substituted by a specific amino acid. The invention also relates to an opioid peptide having the general structure Tyr-A1-B2-C3-NH.sub.2 (SEQ ID NO. 214), wherein A is D-Nve or D-Nle, B is Gly, Phe, or Trp, and C is Trp or Nap. Also included within the invention are opioid peptides of the general structure Me.sub.x H.sub.y N-Tyr-Tyr-Phe.sub.m -Pro.sub.n -NH.sub.2 (SEQ ID NO. 221) which are peptides modified by permethylation, perallylation, perethylation, perbenzylation and/or pernaphthylation and which can be further modified by reduction.

MU opioid receptor ligands: agonists and antagonists

The present invention provides novel opioid peptides. Disclosed are opioid peptides having the general structures Ac-Phe-Arg-Trp-Trp-Tyr-Xaa--NH.sub.2 (SEQ ID NO. 1); Ac-Arg-Trp-Ile-Gly-Trp-Xaa--NH.sub.2 (SEQ ID NO. 2); Trp-Trp-Pro-Lys-His-Xaa--NH.sub.2 (SEQ ID NO. 3); and shorter versions of the latter, namely, Trp-Trp-Pro-Xaa--NH.sub.2 (SEQ ID NO. 4); Tyr-Pro-Phe-Gly-Phe-Xaa--NH.sub.2 (SEQ ID NO. 5); (D)Ile-(D)Met-(D)Ser-(D)Trp-(D)Trp-Gly.sub.n -Xaa--NH.sub.2 (SEQ ID NO. 6); and (D)Ile-(D)Met-(D)Thr-(D)Trp-Gly-Xaa--NH.sub.2 (SEQ ID NO. 7). Within each genus, Xaa is substituted by a specific amino acid. The invention also relates to an opioid peptide having the general structure Tyr-A1-B2-C3--NH.sub.2 (SEQ ID NO. 214), wherein A is D-Nve or D-Nle, B is Gly, Phe, or Trp, and C is Trp or Nap. Also included within the invention are opioid peptides of the general structure Pm and red {Me.sub.x H.sub.y N-Tyr-(NMe).sub.z -Tyr-Xaa.sub.z --NH.sub.2 } (SEQ ID NO. 221), wherein Xaa is substituted by a specific amino acid.

.mu.opioid receptor ligands: agonists and antagonists

The present invention provides novel opioid peptides which are selective for the kappa opiate receptor. In one embodiment, the kappa-selective opioid peptides have the general structure Ac-A1-B2-C3-Arg-Tyr-Arg-Tyr-Arg-Arg-Arg-NH.sub.2, (SEQ ID NO. 28), wherein A1 is Tyr or Arg, B2 is Arg or Phe, and C3 is Thr, Phe, or Met. In yet other embodiments, the kappa-selective opioid peptides have the general structure (D)Phe-D4-E5-F6 (SEQ ID NO. 29) or (D)Nle-D4-E5-F6 (SEQ ID NO. 30), where in both of these formulae D4 is (D)NapAla or (D)Phe, E5 is (D)Nle, Trp, or (D)Ile, and F6 is (D)Arg or (D)ChAla.

Kappa receptor selective opioid peptides

This invention provides novel peptides having the ability to inhibit binding of the mu specific ligand .sup.3 H-[D-Ala.sup.2,MePhe.sup.4,Gly-ol.sup.5 ]enkephalin ('DAGO') to the opioid receptors in crude rat brain homogenate.

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Colette T Dooley