Inhibition of voluntary ethanol consumption with selective melanocortin 4-receptor agonists
The present invention relates to methods of inhibiting or reducing voluntary alcohol consumption in a subject comprising administering a selective melanocortin 4 receptor agonist to said subject. The present invention further relates to methods of treating or preventing alcoholism, alcohol abuse, and alcohol related disorders in a subject comprising administering a selective melanocortin 4 receptor agonist to said subject. The present invention further provides for pharmaceutical compositions and medicaments useful in carrying out these methods.
1 . A method of inhibiting alcohol consumption comprising administering a therapeutically effective amount of a selective melanocortin 4 receptor agonist to a subject in need thereof wherein the selective melanocortin 4 receptor agonist is a compound of Formula I:
wherein:
His is L-histidyl;
D-Phe(X) is D-phenylalanyl unsubstituted or optionally para-substituted with a group selected from F, Cl, Br, Me, and OMe;
Arg is L-arginyl;
W is L-tryptophanyl or 2-naphthyl-L-alanyl;
one of Y and Z is —C(O)— and the other is —NH—;
m is 1 to 4;
n is 1 to 4, provided that n+m is 4 to 6; or
a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 wherein Y is —C(O)— and Z is —NH—.
3 . The method of claim 2 wherein m is 2 and n is 2.
4 . The method of claim 3 selected from:
Z
Y
X
W
m
n
NH
C(O)
H
Trp
4
2
NH
C(O)
H
Trp
3
2
NH
C(O)
H
Trp
2
2
NH
C(O)
H
Trp
1
2
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 4 selected from cyclo(NH—CH 2 —CH 2 —CO-His-D-Phe-Arg-Trp-Glu)-NH 2 , or a pharmaceutically acceptable salt thereof.
6 . A method of reducing alcohol consumption comprising administering a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the selective melanocortin 4 receptor agonist is a compound of Formula I:
wherein:
His is L-histidyl;
D-Phe(X) is D-phenylalanyl unsubstituted or optionally para-substituted with a group selected from F, Cl, Br, Me, and Ome;
Arg is L-arginyl;
W is L-tryptophanyl or 2-naphthyl-L-alanyl;
one of Y and Z is —C(O)— and the other is —NH—;
mis 1 to 4;
n is 1 to 4, provided that n+m is 4 to 6; or
a pharmaceutically acceptable salt thereof.
7 . The method of claim 6 wherein the compound of Formula I is selected from:
or a pharmaceutically acceptable salt thereof.
Z
Y
X
W
m
n
NH
C(O)
H
Trp
4
2
NH
C(O)
H
Trp
3
2
NH
C(O)
H
Trp
2
2
NH
C(O)
H
Trp
1
2
or a pharmaceutically acceptable salt thereof.
8 . The method of claim 7 wherein the compound of Formula I is selected from cyclo(NH—CH 2 —CH 2 —CO-His-D-Phe-Arg-Trp-Glu)-NH 2 , or a pharmaceutically acceptable salt thereof.
9 . A method of treating alcoholism comprising administering a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the selective melanocortin 4 receptor agonist is a compound of Formula I:
wherein:
His is L-histidyl;
D-Phe(X) is D-phenylalanyl unsubstituted or optionally para-substituted with a group selected from F, Cl, Br, Me, and OMe;
Arg is L-arginyl;
W is L-tryptophanyl or 2-naphthyl-L-alanyl;
one of Y and Z is —C(O)— and the other is —NH—;
m is 1 to 4;
n is 1 to 4, provided that n+m is 4 to 6; or
a pharmaceutically acceptable salt thereof.
10 . A method of treating alcohol abuse comprising administering a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the selective melanocortin 4 receptor agonist is a compound of Formula I:
wherein:
His is L-histidyl;
D-Phe(X) is D-phenylalanyl unsubstituted or optionally para-substituted with a group selected from F, Cl, Br, Me, and OMe;
Arg is L-arginyl;
W is L-tryptophanyl or 2-naphthyl-L-alanyl;
one of Y and Z is —C(O)— and the other is —NH—;
mis 1 to 4;
n is 1 to 4, provided that n+m is 4 to 6; or
a pharmaceutically acceptable salt thereof.
11 . A method of inhibiting alcohol consumption comprising administering to a subject in need thereof a therapeutically effective amount of a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
12 . The method of claim 11 wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
13 . The method of claim 11 wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
14 . The method of claim 11 wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
15 . The method of Claim 11 wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
16 - 19 . (canceled)