University of California

Leland Stanford Junior University

Kenneth L Melmon

Murray Edmond Goodman

Michael S Verlander

Roberto P Rosenkranz

Debra Marr-Leisy

Neal Castagnoli

Kenneth Jacobson

Manzoor M Khan

Parisa Khosropour

Michael Verlander

Kenneth A Jacobson

The present invention provides histamine derivatives and methods for using histamine derivatives as immunomodulators and in immunotherapeutics. More specifically the present invention provides methods for inhibiting at least a portion of an an antigen specific antibody response and/or a portion of a T-cell proliferative response by the immune system of a mammal comprising administering to said mammal an effective amount of a composition comprising at least one histamine derivative having binding specificity for at least one histamine receptor.

Histamine derivatives useful as immunomodulators

Histamine derivatives are disclosed which find use as effect and tissue-specific immune modulators. Specifically, the primary terminal nitrogen in histamine is derivatized to introduce a variable length side chain having 0 to 1 branch of from 1 to 3 carbons; 0 to 2 non-oxo-carbonyl groups; 0 to 4 heteroatoms, other than the non-oxo carbonyl oxygen; 0 to 1 aryl or alkyl-aryl group; and 0 to 1 functionally bound amino acid, polypeptide, or protein or derivative thereof.

Histamine derivatives as immune modulators

Molecular structures of .beta.-adrenergic antagonists are modified to produce biologically active compounds. The .beta.-antagonists are modified to form molecules of the general structure: ##STR1## wherein R is most generally R'--OCH.sub.2 --, and in some instances is R'--, and R'=an aryl or substituted aryl moiety; R'=--H, --CH.sub.3, or a short chain alkyl moiety; and Y=--OH, or more usually, --OAX or --NHAX, where A=an alkyl, aryl, or aralkyl moiety, and X=a terminal grouping, such as --CH.sub.3, --CF.sub.3 or --(CH.sub.2).sub.n COOH; or AX may be a carrier moiety consisting of a defined peptide or protein.

Derivatives of .beta.-adrenergic antagonists

Biologically active drugs, e.g. catecholamine hormones, are coupled to carrier molecules, e.g. monodisperse peptides to produce conjugate molecules. The conjugate molecules retain biological activity, but the pharmacokinetic, pharmacodynamic and/or potency properties of the drug is modified. The drug is coupled to the carrier via a spacer moiety which not only serves to covalently link the drug to the carrier, but also insulates the biologically active portion of the drug, i.e., the pharmacophore, from degradation during the coupling process. The carrier preferably consists of a monodisperse peptide in which the sequence of amino acid residues is carefully preselected and controlled.

Drug-carrier conjugates

Biologically active derivatives of norepinephrine are disclosed. Such derivatives are catecholamines wherein isoproterenol is modified by extending the isopropyl functional grouping to an alkyl, aryl, or alkyl-aryl chain of variable length where said chain terminates in a carboxylic acid functional group, or in a substituted amide functional group. Such derivatives are .beta.-adrenergic and a number of such derivatives e.g., 6-(.beta.-3,4-dihydroxyphenyl-.beta.-hydroxy)-ethylamino heptanoic acid p-toluide, 6-(.beta.-3,4-dihydroxyphenyl-.beta.-hydroxy)-ethylamino heptanoic acid para-n-butyl anilide; 6-(.beta.,3,4-dihydroxyphenyl-.beta.-hydroxy)-ethylamino heptanoic acid para-methoxy anilide; 6-(.beta.-3,4-dihydroxyphenyl-.beta.-hydroxy)-ethylamino heptanoic acid paratrifluoromethyl anilide; and 6-(.beta.-3,4-dihydroxyphenyl-.beta.-hydroxy)-ethylamino heptanoic acid N-methyl para-toluide display a .beta.-adrenergic activity at least several orders of magnitude greater than isoproterenol itself. Several methods of producing such active derivatives are also disclosed.

Growing community of inventors

Woodside, CA, United States of America

Kenneth L Melmon