Effects of macrocycle size and rigidity on melanocortin receptor-1 and -5 selectivity in cyclic lactam alpha-melanocyte-stimulating hormone analogs.
The effects of the linker arm rigidity and size on melanocortin receptor selectivity were explored in a series of compounds using cyclic lactam alpha-melanocyte-stimulating hormone template. A variety of dicarboxylic acid linkers introduced between the alpha-amino group of His(6) and the epsilon-amino group of Lys(10) lead to high-affinity, selective human melanocortin receptor-1 and -5 (hMC1R and hMC5R) antagonists. The incorporation of hydrophilic functions into the linker arm was found to be unfavorable for both binding potency and receptor selectivity. Analogs 8 and 9 containing highly conformationally constrained hydrophobic linkers (m- and p-phthalic acids) were found to be selective nanomolar range hMC1R antagonists (IC(50) = 7 and 4 nm, respectively), whereas the employment of a small conformationally constrained linker (maleic acid) resulted in a high-affinity (IC(50) = 19 nm) and selective hMC5R antagonist (analog 12). These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-1 and -5 receptors.
Mayorov
Alexander V
AV
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
Han
So-Yeop
SY
Cai
Minying
M
Hammer
Matthew R
MR
Trivedi
Dev
D
Hruby
Victor J
VJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000737:chemistry; D015394:Molecular Structure; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044101:Receptors, Melanocortin; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D047029:Lactams, Macrocyclic; D044102:Receptor, Melanocortin, Type 1; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D000521:alpha-MSH; D000262:Adenylyl Cyclases