Table 1.

Summary of in Vitro and in Silico Modeled Receptor Binding and in Vivo Tail-Flick Analgesia^a

			K i
compd	R1	R2	MOR-CHO (nM)	MOR in silico (nM)	DOR-CHO (nM)	DOR in silico (nM)	KOR-CHO (nM)	in vivo ED50 (mg/kg)c
4	phenylethyl	cyclopropyl	10.3 ± 5.1	13.79	>100	54.73	87.6 ± 29	0.78 ± 0.26
5	phenylethyl	cyclopentyl	29.4 ± 15	4.29	90.7 ± 23	50.58	>100	9.92 ± 0.08
6	phenylethyl	cyclohexyl	0.84 ± 0.34	0.66	2.65 ± 0.32	44.60	0.44 ± 0.05	3.10 ± 0.19
7	phenylethyl	cycloheptyl	2.66 ± 1.3	3.80	8.90 ± 7.7	7.90	>100	10.0 ± 0.00
8	phenylethyl	butyl	21.1 ± 11	13.38	87.9 ± 4.8	244.5	>100	>10
9	phenylethyl	t-butyl	2.73 ± 2.2	3.65	71.2 ± 8.7	251.0	>100	1.09 ± 0.05
10	phenylethyl	isoamyl	27.0 ± 20	24.15	27.0 ± 3.6	120.4	>100	>10
11	phenylethyl	adamantyl	25.0 ± 9.8	0.88	8.83 ± 0.63	7.65	>100	>10
12	CPMb	cyclohexyl	>100		>100		>100	>10
13	CPMb	t-butyl	>100		>100		>100	>10
DAMGO			3.34 ± 0.43d
morphine			4.6 ± 1.81d					5d
U50,488H							0.73 ± 0.32d
DPDPE					1.39 ± 0.67d

^aCompetition studies were performed with the indicated compounds against ¹²⁵I-BNtxA (0.1 nM) in membranes from CHO cells stably expressing the indicated cloned mouse opioid receptors. K_i values were calculated from the IC₅₀ values¹⁸ and represent the means ± SEM of at least three independent replications. In silico Inhibitory constants were calculated from the binding free energies obtained from docking (vide infra) according to the following equation: ΔH = RT ln K_i. ¹²⁵IBNtxA K_D values for MOR, KOR, and DOR sites were 0.11, 0.03, and 0.24, respectively.

^bCPM = cyclopropylmethyl.

^cAnalgesia was determined using the radiant heat tail-flick technique on CD-1 mice as described in the Methods section.

^dValues from literature ref 25.