Table 1.

Functional Activity of the DPhe⁷ (α-MSH Numbering) Modified Tetrapeptides at the Mouse Melanocortin Receptors^a

peptide	structure	mMC1R		mMC3R		mMC4R		mMC5R
		EC50 (nM)	fold diffb	EC50 (nM)	fold diffb	EC50 (nM)	fold diffb	EC50 (nM)	fold diffb
NDP-MSH	Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2	0.088 ± 0.031		0.33 ± 0.08		0.12 ± 0.01		0.26 ± 0.05
5	Ac-His-DPhe7-Arg-Trp-NH2	112 ± 28	1	126 ± 7.8	1	2.28 ± 0.52	1	3.26 ± 0.60	1
6	Ac-His-DTyr-Arg-Trp-NH2Tyr	2600 ± 930	23	12500 ± 5700	99	390 ± 48	171	730 ± 210	223
7	Ac-His-DPhe(pNH2)-Arg-Trp-NH2	2300 ± 300	21	16400 ± 1480	130	220 ± 15.0	96	226 ± 10.2	69
8	Ac-His-DPhe(pCH3)-Arg-Trp-NH2	170 ± 20	2	525 ± 130	4	5.65 ± 0.88	2	5.20 ± 0.71	2
9	Ac-His-DPhe(pt-Bu)-Arg-Trp-NH2	100 ± 13	1	>100000c		4360 ± 1300	1912	340 ± 73	104
10	Ac-His-DPhe(pBz)-Arg-Trp-NH2	180 ± 72	2	770 ± 108	6	63.8 ± 12.5	28	51.1 ± 3.22	16
11	Ac-His-DPhe(pCN)-Arg-Trp-NH2	280 ± 27	3	240 ± 49	2	2.84 ± 0.26	1	2.85 ± 0.27	1
12	Ac-His-DPhe(pNO2)-Arg-Trp-NH2	1030 ± 145	9	615 ± 44	5	13.0 ± 2.92	6	17.6 ± 2.1	5
13	Ac-His-DPhe(pF)-Arg-Trp-NH2	53.7 ± 8.62	−2d	53.7 ± 5.30	−2d	0.45 ± 0.10	−5d	2.04 ± 0.27	−2d
14	Ac–His-DPhe(pCl)-Arg-Trp-NH2	38.2 ± 3.3	−3d	84.8 ± 21.0	−2d	0.40 ± 0.12	−6d	1.47 ± 0.44	−2d
15	Ac-His-DPhe(pBr)-Arg-Trp-NH2	40.8 ± 10.4	−3d	~50% at 100 μMe pA2 = 7.54 ± 0.12f	antagonist Ki = 350 nM	1.07 ± 0.46	−2d	2.60 ± 1.52	1
16	Ac-His-DPhe(pI)-Arg-Trp-NH2	40.7 ± 2.73	3	~40% at 100 μMe pA2 = 7.41 ± 0.08f	antagonist Ki = 260 nM	3.94 ± 1.32	2	7.41 ± 0.08	2
17	Ac-His-DPhe(pCF3)-Arg-Trp-NH2	540 ± 120	5	~25% at 100 μMe pA2 = 6.79 ± 0.15f	antagonist Ki = 6170 nM	12.8 ± 1.94	6	8.03 ± 1.33	2
18	Ac-His-DNal(2′)-Arg-Trp-NH2	92.8 ± 42.7	1	~25% at 100 μMe pA2 = 6.70 ± 0.12f	antagonist Ki = 5010 nM	pA2 = 8.28 ± 0.13	antagonist Ki = 19 nM	22.4 ± 5.0	7
19	Ac-His-DPhe(3,4-diCl)-Arg-Trp-NH2	140 ± 30	1	~30% at 100 μMe pA2 = 7.42 ± 0.26f	antagonist Ki = 260 nM	3.40 ± 0.66	1	7.42 ± 0.26	2
20	Ac-His- DPhe(m-Cl)-Arg-Trp-NH2	320 ± 57.3	3	1240 ± 270	10	8.64 ± 1.73	4	30.0 ± 13.6	9

^aThe indicated errors represent the standard error of the mean from at least three independent experiments.

^bThe fold differences are determined relative to compound 5.

^cCompounds possessing >100000 EC₅₀ values were not found to possess agonist or antagonist activity at up to 100 μM concentrations.

^dA negative fold difference is indicative of increased potency relative to compound 5.

^eA percentage value indicates that some stimulatory agonist pharmacology resulted at up to 100 μM concentrations, but the maximal stimulation levels were less than the control level.

^fThe compounds not demonstrating full agonism were assayed for antagonism using Schild pA₂ analysis and the MTII peptide as agonist. K_i = −log pA₂.