Table 1.

In vitro and in vivo opioid activity of N-methylmorphinan-6-ones 1–4 and their 6-desoxo counterparts 1a–4a.

	Binding Affinity (Ki, nM) a				MOP Agonist Activity b		Antinociception c
	MOP	DOP	KOP	Ki Ratios MOP/DOP/KOP	EC50 (nM)	% stim.	ED50 (µg/kg, s.c.)
1	1.79	70.0	25.3	1/39/14	7.80	91.5	382
1a	1.65	201	21.6	1/1122/13	8.99	104	383
2	0.32	8.80	10.1	1/28/32	1.45	96.4	14.2
2a	0.24	8.64	3.99	1/36/17	1.37	105	17.3
3	0.45	1.05	1.27	1/2.3/1.8	0.32	101	2.38
3a	0.048	0.89	0.85	1/21/18	0.13	103	2.41
4	0.25	19.8	15.1	1/79/60	3.28	99.2	27.1
4a	0.34	12.9	7.92	1/38/23	2.95	104	25.1

^a Determined in competition radioligand binding assays using membranes of CHO cells stably expressing the human opioid receptors. ^b Determined in the [³⁵S]GTPγS binding assay using CHO-hMOP cell membranes; percentage stimulation relative to the standard MOP receptor agonist DAMGO. ^c Determined in the hot-plate assay in mice after s.c. administration. Data from [66]. For compound structures, refer to Scheme 1.