Peptide mimetics of thyrotropin-releasing hormone based on a cyclohexane framework: design, synthesis, and cognition-enhancing properties.
The design and synthesis of peptide mimetics of thyrotropin-releasing hormone (TRH) in which the peptide backbone is entirely replaced by a cyclohexane framework are described. The cis-1,3,5-trisubstituted ring was expected to permit key pharmacophoric groups to adopt conformations consistent with proposed bioactive conformations of the peptide. Compounds were synthesized by a stereoselective synthesis starting from L-glutamic acid. In a behavioral model of cognition in which TRH is active, the mimetics are potent, active compounds, exhibiting oral activity. One analog (26, (1S,3R,5(2S),5S)-5-[[5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-methyl]-5- [(1H-imidazol-5-yl)methyl]cyclohexaneacetamide) was radiolabeled for binding studies and evaluated in other binding assays and pharmacological tests. Competition binding of 26 vs [3H]MeTRH to rat brain slices suggests a two-site model for ligand binding with IC50's of 1 microM and 3 mM. Direct binding of [3H]-26 shows a biphasic curve with IC50's of 80 and 49 microM, respectively. Further studies would be needed to establish a link between the novel binding site(s) and the behavioral activity of 26 and TRH analogs.
Olson
G L
GL
Chemistry Research Department, Hoffmann-La Roche Inc., Roche Research Center, Nutley, New Jersey 07110, USA.
Cheung
H C
HC
Chiang
E
E
Madison
V S
VS
Sepinwall
J
J
Vincent
G P
GP
Winokur
A
A
Gary
K A
KA
D000595:Amino Acid Sequence; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy*; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000502:physiology*
D003510:Cyclohexanes; D010455:Peptides; D013973:Thyrotropin-Releasing Hormone