Table 2.

Pharmacology of the macrocyclic AGRP-based peptides modified in the Phe⁷ position [Pro¹-Arg²-Phe³-Phe⁴-Asn⁵-Ala⁶-Phe⁷-DPro⁸].

Compound ID	KAF#	R7	Agonist	Antagonist		Antagonist		Inverse Agonist
			mMC1R	mMC3R		mMC4R		mMC5R
			Agonist EC50 (nM)	pA2	Antagonist Ki (nM)	pA2	Antagonist Ki (nM)	Inverse Agonist EC50 (nM)
NDP-MSH			0.010±0.003	EC50 = 0.06±0.01 nM		EC50 = 0.35±0.06 nM		EC50 = 0.10±0.01 nM
hAGRP(87-132)a			> 100,000	8.9±0.2	1.3	9.4±1.0	0.40	> 100,000
1b	MDE5108-10c	Phe	25% @ 100 μM	6.3±0.1	500	8.2±0.1	6.3	130 (−10%)
2	KAF2039-1	Gly	60% @ 100 μM	< 5.5		6.17±0.04	680	−25% @ 100 μM
3	KAF2039-3	Ser	35% @ 100 μM	6.0±0.2	1,000	7.2±0.2	63	−55% @ 100 μM
4	KAF2039-4	Lys	> 100,000	5.7±0.1	2,000	6.60±0.06	250	−40% @ 100 μM
5	KAF2039-5	Asp	40% @ 100 μM	< 5.5		< 5.5		−25% @ 100 μM
6	KAF2039-6	Leu	> 100,000	< 5.5		7.03±0.09	93	−35% @ 100 μM
7	KAF2039-7	Nle	> 100,000	6.1±0.1	790	8.4±0.2	4.0	−35% @ 100 μM
8	KAF2039-9	Trp	partial agonist 1,100 ± 200 (50%)	6.67±0.07	210	8.2±0.2	6.3	150 (−20%)
9	KAF2039-10	Tyr	> 100,000	6.23±0.05	590	8.00±0.06	10	−40% @ 100 μM
10	KAF2039-11	Cha	> 100,000	5.8±0.2	1,600	7.0±0.03	100	780 (−20%)
11	KAF2039-13	hPhe	> 100,000	6.5±0.3	320	7.30±0.06	50	290 (−20%)
12b	KAF3094	Ala	> 100,000	6.1±0.2	790	8.2±0.1	6.3	−25% @ 100 μM

Compounds were assayed in duplicate replicates and values are expressed as the mean ± the standard error of the mean (SEM) of at least 3 independent experiments. “Partial agonist”: partial agonist activity, with a maximal percent activated listed in parenthesis. “X% @ 100 μM”: Compounds that partially stimulated the receptor but were unable to generate a sigmoidal dose-response at 100 μM concentrations are listed by their percent activation at 100 μM. “> 100,000”: Compounds which showed no agonist activity at 100 μM are listed as > 100,000. “< 5.5”: The use of <5.5 indicates that no antagonist potency was observed in the highest concentration ranged assayed (10,000, 5,000, 1,000, and 500 nM). “X (-X%)”: For compounds that displayed inverse agonist activity and appeared to generate a sigmoidal dose-response, the average apparent potency at the inflection point and maximal decrease in basal activity at the plateau is listed. “-X% @ 100 μM”: For all other compounds with inverse agonist activity, the percent decrease observed in receptor activity compared to basal at 100 μM is provided. The pA₂ values were determined using the Schild analysis with agonist NDP-MSH (pA₂ = −log[K_i]).

^aThis peptide has been previously published.⁴⁸

^bThese peptides have been previously reported.⁵⁶