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Article

Structure−Activity Relationships of Novel Cyclic α-MSH/β-MSH Hybrid Analogues That Lead to Potent and Selective Ligands for the Human MC3R and Human MC5R

Supporting Info

Preeti Balse-Srinivasan,^†^‡ Paolo Grieco,^†^§ Minying Cai,^† Dev Trivedi,^† and Victor J. Hruby*^†

Department of Chemistry, University of Arizona, Tucson, Arizona 85721 and Department of Pharmaceutical Chemistry, University of Napoli Federico II, Via D. Montesano, 49, 80131 Napoli, Italy

J. Med. Chem., 2003, 46 (17), pp 3728–3733

DOI: 10.1021/jm030111j

Publication Date (Web): July 23, 2003

†

University of Arizona.

‡

Current address: Bexel Pharmaceuticals, Inc., 32990 Alvarado Niles Rd., Suite 910, Union City, CA 94587.

Current address: Department of Pharmaceutical Chemistry and Toxicology, University of Napoli “Federico II”, Napoli 80131, Italy.

To whom correspondence should be addressed: Phone: (520) 621-6332. Fax: (520) 621-8407. E-mail: hruby@u.arizona.edu.

Abstract

It has been shown by extensive studies that α-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R. The structure−activity relationships study here is aimed at identifying lead structures or templates of this core sequence by the use of different conformational constraints that might impart changes in its topography and thus promote differences in potency and selectivity at these receptors. Our peptide library consists of a novel series of cyclic α-MSH analogues that have disulfide bridges between Cys or Cys-like residues at positions 4 and 10, giving rise to 23-membered rings fused at the C-terminal end with the C-terminal fragment of β-MSH (Pro-Pro-Lys-Asp). While such constraints of the peptide backbone with disulfide bridges of different chirality affect potency and selectivity at these receptors, further changes in the hydrophobicity at position 7 with either a d-Phe or d-Nal(2‘) and replacement of a His with a Pro in position 6 cause additional effects. Thus, the most interesting lead compounds that emerged from this study are (1) compound 5, Ac-c[Cys-Glu-His-d-Phe-Arg-Trp-d-Cys]-Pro-Pro-Lys-Asp-NH₂ (IC₅₀ = 10 nM), which is the first potent and highly selective antagonist ligand for the hMC5R (560-fold vs the MC3R and 1000-fold vs the MC4R); (2) compound 7, Ac-c[Cys-Glu-Pro-d-Nal(2‘)-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH₂ (IC₅₀ = 31 nM), which is a highly selective antagonist analogue for the MC3R (560-fold vs the hMC4R and about 3000-fold vs the hMC5R; and (3) compound 9, Ac-c[Pen-Glu-His-d-Nal(2‘)-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH₂ (IC₅₀ = 3 nM), which is more potent than 7 at the MC3R but not as selective.