Table 1.

Binding affinities and functional activities of bifunctional NOP/opioid ligands

Structure		Receptor Binding Ki (nM)			[35S]GTPγS NOP		[35S]GTPγS μ		[35S]GTPγS κ
		NOP	μ	κ	EC50 nM	% Stim	EC50 nM	% Stim	EC50 nM	% Stim
C-moietypharmaeophore (pipetidine N-substituent) modifications
1		1.39 ± 0.42	29.9 ± 2.09	42.7 ± 1.02	20.8 ± 3.1	54 ± 11	99 ± 12	23.4 ± 3	276 ± 75	38 ± 3
2		7.49 ± 0.78	2.70 ± 0.05	31.74 ± 4.8	28.7 ± 0.6	45 ± 5	29 ± 10	30 ± 0.2	<10K
3		3.96 ± 1.55	8.0 ± 0.97	148.7 ± 8.7	26.5 ± 4.3	100± 15	73.5 ± 5	49 ± 0.45	<10K
4		7.63 ± 1.87	5.39 ± 0.16	190.2 ± 45	107 ± 8	62 ± 6	595±493	28 ± 8	NTa	NT
5		15.26 ± 0.29	16.13 ± 1.2	159.7 ± 4.2	83 ± 2	18.5 ± 2	189 ± 78	39 ± 6	NT	NT
6		212.8 ± 0.95	533 ± 42.3	NTa	NT	NT	NT	NT	NT	NT
7		9.98 ± 2.8	3.44 ± 0.46	43.9 ± 9.2	82.3 ± 16	60± 10	28 ± 3.4	80.5 ± 11	873±293	48 ± 12
8		201.3 ± 51.7	91.1 ± 16.6	84.5 ± 0.76	174 ± 51	18± 2	1981±606	36 ± 5	<10K
9		26.9 ± 0.25	2.34 ± 0.45	29.2 ± 0.06	138 ± 34	76± 14	50.6 ± 7	91 ± 4.9	422.60	37.5
10		11.43 ± 0.91	79.9 ± 3.86	681.3 ± 61	46.1 ± 20	107± 7.4	129 ± 48	18 ± 1.6	<10K

A-moietypharmaeophore (thepipetidine 4-position heterocyclic ring)
11		6.53 ± 1.48	3.62 ± 0.38	41.77 ± 2.4	54.9 ± 41	100± 40	119.6	84.3	<10K
12		12.65 ± 1.93	10.49 ± 0.4	39.2 ± 15.3	30.2 ± 0.3	40± 10	94 ± 1.4	53.2± 14	<10K
13		5.22 ± 0.65	1.07 ± 0.17	82.4 ± 16.4	8.5 ± 0.8	95± 12	4.7 ± 1.2	44 ± 5.2	<10K
14		8.67 ± 0.89	16.26 ± 5.2	43.4 ± 17.8	6.8 ± 0.96	62 ± 12	37.3 ± 5	63 ± 18	<10K
15		20.4 ± 5.55	7.62 ± 1.01	70.04 ± 8.4	127 ± 5.3	75± 5	68 ± 5.9	50 ± 0.55	<10K
16		18.66 ± 5.05	46.97 ± 5.4	37.92 ± 32	101 ± 20	32 ± 2.2	NT	NT	<10K
17		40.28 ± 1.8	23.27 ± 0.7	27.69 ± 3.6	94.7 ± 12	38 ± 2	58 ± 18	59 ± 5.1	<10K

^aNT=not tested. In some cases where the binding affinity was above 40 nM, the functional assays were not done.