Method of treating melanocortin-4 receptor pathway-associated disorders

A method of treating a disorder in a subject in need thereof, comprising:

• administering an agonist of the melanocortin-4 receptor (MC4R) at a daily dosage of about 0.1 mg to about 10 mg,
• wherein the disorder is characterized by one or more mutations in a gene associated with Bardet-Biedl syndrome,
• wherein the agonist is a MC4R agonist having a structure of Formula (I)
• (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1 (I),
• wherein:
• A1 is Acc, HN—(CH2)m—C(O), L- or D-amino acid, or deleted;
• A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;
• A3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or deleted;
• A4 is H is, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X1, X2, X3, X4, X5)Phe;
• A5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X1, X2, X3, X4, X5)Phe, L-Phe or D-(Et)Tyr;
• A6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN—CH((CH2)n—N(R4R5))—C(O);
• A7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal or D-Bip;
• A8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN—(CH2)s—C(O), or deleted;
• A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;
• A10 is Acc, HN—(CH2)r—C(O), L- or D-amino acid, or deleted;
• R1 is OH or NH2;
• each of R2 and R3 is, independently for each occurrence, selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C1-C30)acyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, substituted aryl(C1-C30)alkyl, and substituted aryl(C1-C30)acyl;
• each of R4 and R5 is, independently for each occurrence, H, (C1-C40)alkyl, (C1-C40)heteroalkyl, (C1-C40)acyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, aryl(C1-C40)acyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C1-C40)acyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, substituted aryl(C1-C40)alkyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl, or —C(NH)—NH2;
• m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
• n is, independently for each occurrence, 1, 2, 3, 4 or 5;
• s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
• t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
• X′, X2, X3, X4, and X8 each is, independently for each occurrence, H, F, Cl, Br, I, (C1-10)alkyl, substituted (C1-10)alkyl, (C2-10)alkenyl, substituted (C2-10)alkenyl, (C2-10)alkynyl, substituted (C2-10)alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.