Growth Hormone Releasing Peptides

Abstract

Disclosed are peptide and peptidomimetic compounds generally according to formula (I) that are useful as GHRP analogs: R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2    (I) wherein: A 1 is Aib, Apc or Inp; A 2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A 3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A 4 is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); A 5 is Apc, Dab, Dap, Lys, Orn, or deleted; R 1 is hydrogen, (C1-6)alkyl, (C5-14)aryl, (C1-6)alkyl(C5-14)aryl, (C3-8)cycloakyl, or (C2-10)acyl; and R 2 is OH or NH 2 ; and pharmaceutical compositions and methods of use thereof.

What is claimed is: 
     
         1 . A compound according to formula (I):
   R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2    (I)
   
       or a pharmaceutically acceptable salt thereof, wherein:
 A 1  is Inp; 
 A 2  is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; 
 A 3  is D-Bal or D-Trp; 
 A 4  is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, or Thr(Bzl); 
 A 5  is Apc or Lys; 
 R 1  is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and 
 R 2  is OH or NH 2 ; 
 
       provided that:
 when A 5  is Lys, then:
 A 2  is D-Bip, D-Bpa, D-Dip or D-Bal; or 
 A 3  is D-Bal; or 
 A 4  is 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl), or Pff. 
 
 
     
     
         2 . A compound according to  claim 1 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;   H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;   H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;   H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;   H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;   H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;   H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;   H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;   H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;   H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;   H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;   H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;   H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;   H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;   H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;   H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;   H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;   H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;   H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;   H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;   H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;   H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;   H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;   H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;   H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;   H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;   H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;   H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;   H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;   H-Inp-D-Bip-D-Trp-Pff-Lys-NH2; or   H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A compound according to  claim 2 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;   H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;   H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;   H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;   H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;   H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;   H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;   H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;   H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;   H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;   H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;   H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;   H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;   H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;   H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;   H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;   H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;   H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;   H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;   H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;   H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;   H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;   H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;   H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;   H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;   H-Inp-D-Bip-D-Trp-Pff-Lys-NH2;   H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;   H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;   H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;   H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2; or   H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . A compound according to  claim 3 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;   H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;   H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2; or   H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A compound according to  claim 4 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;   H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2; or   H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A compound according to  claim 5 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;   H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2; or   H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         7 . A compound according to  claim 6 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;   H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2; or   H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A compound according to  claim 7 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         9 . A compound according to  claim 4 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;   H-Inp-D-Dip-D-Trp-Phe-Lys-NH2; or   H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         10 . A compound according to  claim 9 , wherein said compound is according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2; or   H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         11 . A compound according to the formula:
 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;   H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2; or   H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . A method for stimulating growth hormone secretion in a subject in need of such stimulation, said method comprising the step of administering to said subject an effective amount of a compound according to formula (I):
   R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2    (I)
   or a pharmaceutically acceptable salt thereof, wherein:   A 1  is Inp;   A 2  is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp;   A 3  is D-Bal or D-Trp;   A 4  is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl);   A 5  is Apc or Lys;   R 1  is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and   R 2  is OH or NH 2 ;   
       provided that:
 when A 5  is Lys, then:
 A 2  is D-Bip, D-Bpa, D-Dip or D-Bal; or 
 A 3  is D-Bal; or 
 A 4  is 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl), or Pff, 
 
 wherein said effective amount is at least an amount sufficient to produce a detectable increase in growth hormone secretion and, preferably, is an amount sufficient to achieve a beneficial effect in a patient. 
 
     
     
         13 . A method according to  claim 12  wherein said stimulation of growth hormone secretion is indicated for treatment of a growth hormone deficient state, for increasing muscle mass, for increasing bone density, for sexual dysfunction in males or females, for facilitating a weight gain, for facilitating maintenance of weight, for facilitating maintenance of physical functioning, for facilitating recovery of physical function, and/or facilitating appetite increase. 
     
     
         14 . A method according to  claim 13  wherein said facilitating weight gain, facilitating maintenance in weight, and/or facilitating appetite increase is indicated in a patient having a disease or disorder, or undergoing a treatment, accompanied by weight loss. 
     
     
         15 . A method according to  claim 14  wherein said diseases or disorders accompanied by weight loss include anorexia, bulimia, cancer cachexia, AIDS, AIDS wasting, cachexia, and wasting in frail elderly. 
     
     
         16 . A method according to  claim 14  wherein said treatments accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization, and dialysis. 
     
     
         17 . A method for achieving a beneficial cardiovascular effect in a subject in need thereof, said method comprising the step of administering to said subject an effective amount of a compound according to formula (I):
   R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2    (I)
   or a pharmaceutically acceptable salt thereof, wherein:   A 1  is Inp;   A 2  is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp;   A 3  is D-Bal or D-Trp;   A 4  is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl);   A 5  is Apc or Lys;   R 1  is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and   R 2  is OH or NH 2 ;   
       provided that:
 when A 5  is Lys, then:
 A 2  is D-Bip, D-Bpa, D-Dip or D-Bal; or 
 A 3  is D-Bal; or 
 A 4  is 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl), or Pff, 
 
 wherein said effective amount is at least an amount sufficient to produce a beneficial cardiovascular effect in said subject. 
 
     
     
         18 . A method according to  claim 17  wherein said beneficial cardiovascular effect comprises inhibition of apoptosis of cardiomyocytes, cardiac endothelial cells, or vascular endothelial cells. 
     
     
         19 . A method according to  claim 17  wherein said beneficial cardiovascular effect comprises improvement of cardiac structure or function. 
     
     
         20 . A method according to  claim 17  wherein said beneficial cardiovascular effect comprises attenuation of the development of cardiac cachexia. 
     
     
         21 . A method according to  claim 17  wherein said beneficial cardiovascular effect comprises a reduction in systemic vascular resistance. 
     
     
         22 . A method according to  claim 17  wherein said beneficial cardiovascular effect comprises an increase in cardiac output. 
     
     
         23 . A method according to  claim 17 , wherein said subject comprises a human. 
     
     
         24 . A method according to  claim 23 , wherein said human suffers from chronic heart failure or severe chronic heart failure. 
     
     
         25 . A method for suppressing growth hormone secretion in a subject in need of such suppression, comprising the step of administering to said subject an effective amount of a compound according to formula (I):
   R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2    (I)
   or a pharmaceutically acceptable salt thereof, wherein:   A 1  is Inp;   A 2  is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp;   A 3  is D-Bal or D-Trp;   A 4  is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl);   A 5  is Apc or Lys;   R 1  is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and   R 2  is OH or NH 2 ;   
       provided that:
 when A 5  is Lys, then:
 A 2  is D-Bip, D-Bpa, D-Dip or D-Bal; or 
 A 3  is D-Bal; or 
 A 4  is 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl), or Pff, 
 
 wherein said effective amount is at least an amount sufficient to produce a detectable decrease in growth hormone secretion and, preferably, is an amount sufficient to achieve a beneficial effect in a patient. 
 
     
     
         26 . A method according to  claim 25  wherein said suppression of growth hormone secretion is indicated for the treatment of a disease or condition characterized by excessive growth hormone secretion, for facilitation of weight loss, for facilitation of appetite decrease, for facilitation of weight maintenance, for treating obesity, for treating diabetes, for treating complications of diabetes including retinopathy, and/or for treating cardiovascular disorders. 
     
     
         27 . A method according to  claim 26  wherein said excessive weight is a contributing factor to a disease or condition including hypertension, diabetes, dyslipidemia, cardiovascular disease, gall stones, osteoarthritis and cancers. 
     
     
         28 . A method according to  claim 27  wherein said facilitation of weight loss reduces the likelihood of such diseases or conditions. 
     
     
         29 . A method according to  claim 27  wherein said facilitation of weight loss comprises at least part of a treatment for such diseases or conditions. 
     
     
         30 . A method of eliciting a ghrelin agonist effect in a subject, comprising the step of administering to a subject an effective amount of a ghrelin agonist according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable increase in growth hormone secretion. 
     
     
         31 . A method of eliciting a ghrelin antagonist effect in a subject, comprising the step of administering to a subject an effective amount of a ghrelin antagonist according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable decrease in growth hormone secretion.