Neo-tryptophan

Abstract

The invention provides a novel amino acid, neo-tryptophan, as well as polypeptides containing this novel amino acid such as neurotensin analogs. In addition, the invention provides neo-tryptophan derivatives, serotonin-like neo-tryptophan derivatives, and polypeptides containing such derivatives. The invention also provides methods for making neo-tryptophan, neo-tryptophan derivatives, serotonin-like neo-tryptophan derivatives, and compositions containing these compounds. Further, the invention provides methods for inducing a neurotensin response in a mammal as well as methods for treating a mammal having a serotonin recognition molecule.

What is claim ed is:  
     
         1 . A polypeptide, wherein said polypeptide comprises neo-tryptophan.  
     
     
         2 . The polypeptide of    claim 1   , wherein said polypeptide is substantially pure.  
     
     
         3 . The polypeptide of    claim 1   , wherein said neo-tryptophan is L-neo-tryptophan.  
     
     
         4 . The polypeptide of    claim 1   , wherein said neo-tryptophan is D-neo-tryptophan.  
     
     
         5 . The polypeptide of    claim 1   , wherein said polypeptide interacts with a neurotensin receptor.  
     
     
         6 . The polypeptide of    claim 1   , wherein said polypeptide is a neurotensin analog with neo-tryptophan being located at amino acid position 11 of neurotensin.  
     
     
         7 . The polypeptide of    claim 1   , wherein said polypeptide is selected from the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT69L′, NT71, NT72, NT73, NT74, NT75, NT76, NT77, Angl, Brdyl, and Lenkl.  
     
     
         8 . An amino acid, wherein said amino acid is neo-tryptophan.  
     
     
         9 . The amino acid of    claim 8   , wherein said amino acid is substantially pure.  
     
     
         10 . The amino acid of    claim 8   , wherein said amino acid is L-neo-tryptophan.  
     
     
         11 . The amino acid of    claim 8   , wherein said amino acid is D-neo-tryptophan.  
     
     
         12 . A neo-tryptophan derivative.  
     
     
         13 . The neo-tryptophan derivative of    claim 12   , wherein said derivative comprises neo-tryptophan and a blocking group.  
     
     
         14 . The neo-tryptophan derivative of    claim 13   , wherein said blocking group comprises Fmoc.  
     
     
         15 . The neo-tryptophan derivative of    claim 13   , wherein said blocking group comprises Boc.  
     
     
         16 . A serotonin-like neo-tryptophan derivative, said derivative comprising the following structure: 
                   wherein R 1 , R 2 , and R 3  is H, OH, CH 3 , SH, F, NH 2 , or COOH, and A is zero, one, two, or three.    
     
     
         17 . The serotonin-like neo-tryptophan derivative of    claim 16   , wherein R 1  and R 3  each is a hydroxyl group, R 2  is an amino group, and A is zero.  
     
     
         18 . A method of synthesizing neo-tryptophan, said method comprising: 
 a) providing 4-hydroxymethyl indole, and    b) substituting the hydroxyl group of said 4-hydroxymethyl indole with a glycyl unit to produce neo-tryptophan.    
     
     
         19 . The method of    claim 18   , wherein the N-1 nitrogen of said 4-hydroxymethyl indole is protected by a protecting group, said method comprising removing said protecting group after said substitution.  
     
     
         20 . The method of    claim 19   , wherein said protecting group comprises Boc.  
     
     
         21 . The method of    claim 18   , wherein said method comprises: 
 a) providing 2-methyl-3-nitrobenzoic acid,    b) esterifying said 2-methyl-3-nitrobenzoic acid to form an esterification product,    c) reacting said esterification product with N,N-dimethylformamide dimethylacetal to produce an enamine product,    d) performing reductive cyclization on said enamine product to produce a 4-substituted indole methyl ester,    e) protecting the indole nitrogen of said 4-substituted indole methyl ester with a Boc group,    f) reducing said protected 4-substituted indole methyl ester with DIBAL to produce N-Boc-4-hydroxymethyl indole,    g) converting said N-Boc4-hydroxymethyl indole into benzylic bromide,    h) performing SN 2  displacement of the bromide of said benzylic bromide with a carbanion to produce diastereomeric bislactim products,    i) isolating one of said diastereomeric bislactim products,    j) hydrolyzing said isolated diastereomeric bislactim product to produce an aminoester product,    k) saponifying said aminoester product to produce an N ind -t-Boc amino acid, and    l) removing the Boc group to produce neo-tryptophan.    
     
     
         22 . A method of synthesizing a neo-tryptophan derivative, said method comprising: 
 a) providing 4-hydroxymethyl indole, wherein the N-1 nitrogen of said 4-hydroxymethyl indole is protected by a protecting group, and    b) substituting the hydroxyl group of said 4-hydroxymethyl indole with a glycyl unit to produce a neo-tryptophan derivative.    
     
     
         23 . The method of    claim 22   , wherein said protecting group comprises Boc.  
     
     
         24 . The method of    claim 22   , wherein said method comprises adding, after said substitution, an additional protecting group to the nitrogen within said glycyl unit.  
     
     
         25 . The method of    claim 24   , wherein said additional protecting group comprises Fmoc.  
     
     
         26 . A method of making a polypeptide containing neo-tryptophan, said method comprising: 
 a) providing a neo-tryptophan derivative, and    b) linking an amino acid residue to said neo-tryptophan derivative to form said polypeptide containing neo-tryptophan.    
     
     
         27 . The method of    claim 26   , wherein said neo-tryptophan derivative contains a blocking group attached to a nitrogen atom.  
     
     
         28 . The method of    claim 26   , wherein said neo-tryptophan is L-neo-tryptophan.  
     
     
         29 . The method of    claim 26   , wherein said neo-tryptophan is D-neo-tryptophan.  
     
     
         30 . A method of inducing a neurotensin response in a mammal, said method comprising administering an effective dose of a polypeptide to said mammal, wherein said polypeptide comprises neo-tryptophan.  
     
     
         31 . The method of    claim 30   , wherein said mammal is a human.  
     
     
         32 . The method of    claim 30   , wherein said administration is extracranial.  
     
     
         33 . The method of    claim 30   , wherein said administration is an intraperitoneal, intravenous, intradermal, subcutaneous, oral, or nasal administration.  
     
     
         34 . The method of    claim 30   , wherein said response comprises antinociception.  
     
     
         35 . The method of    claim 30   , wherein said response comprises hypothermia.  
     
     
         36 . The method of    claim 30   , wherein said response comprises a reduction in appetite.  
     
     
         37 . The method of    claim 30   , wherein said response comprises a reduction in body weight.  
     
     
         38 . The method of    claim 30   , wherein said response comprises a reduction in body weight gain.  
     
     
         39 . The method of    claim 30   , wherein said response comprises preventing or reducing catalepsy.  
     
     
         40 . The method of    claim 30   , wherein said response comprises reducing an effect of a CNS stimulant.  
     
     
         41 . The method of    claim 40   , wherein said CNS stimulant comprises apomorphine.  
     
     
         42 . The method of    claim 41   , wherein said effect comprises a climbing behavior.  
     
     
         43 . The method of    claim 40   , wherein said CNS stimulant is selected from the group consisting of amphetamine and cocaine.  
     
     
         44 . The method of    claim 30   , wherein said response comprises an antipsychotic effect.  
     
     
         45 . The method of    claim 44   , wherein said polypeptide reduces the signs or symptoms of schizophrenia in said mammal.  
     
     
         46 . The method of    claim 30   , wherein said polypeptide interacts with a neurotensin receptor.  
     
     
         47 . The method of    claim 46   , wherein said neurotensin receptor is a rat neurotensin receptor.  
     
     
         48 . The method of    claim 46   , wherein said neurotensin receptor is a human neurotensin receptor.  
     
     
         49 . The method of    claim 30   , wherein said polypeptide is selected from the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT69L′, NT71, NT72, NT73, NT74, NT75, NT76, and NT77.  
     
     
         50 . A method of treating a mammal having a serotonin recognition molecule, said method comprising administering a composition to said mammal, wherein said composition interacts with said serotonin recognition molecule, said composition comprising a compound selected from the group consisting of neo-tryptophan, neo-tryptophan derivatives, and serotonin-like neo-tryptophan derivatives.  
     
     
         51 . The method of    claim 50   , wherein said mammal is a human.  
     
     
         52 . The method of    claim 50   , wherein said composition comprises a polypeptide.  
     
     
         53 . The method of    claim 50   , wherein said serotonin recognition molecule comprises a serotonin receptor.  
     
     
         54 . The method of    claim 53   , wherein said serotonin receptor is a 5HT 2A  receptor.  
     
     
         55 . A method for screening a polypeptide for in vivo use, said method comprising: 
 a) contacting a polypeptide with a protease, wherein said polypeptide contains neo-tryptophan, and    b) determining whether or not said polypeptide remains intact.    
     
     
         56 . The use of a polypeptide in the manufacture of a medicament for treating a mammal, said polypeptide comprising neo-tryptophan.  
     
     
         57 . The use of a compound in the manufacture of a medicament for treating a mammal, said compound being selected from the group consisting of neo-tryptophan, neo-tryptophan derivatives, and serotonin-like neo-tryptophan derivatives.