Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile

Table 1

In vitro and in vivo opioid activity and SAR study on the variation of the substituent in position 5 in 14-alkoxy-substituted N-methylmorphinan-6-ones.

		Binding affinity (Ki, nM)					Agonist potency; (relative to morphine)
	R1, R2, R3	MOR^a	DOR^b	KOR^d	Selectivity		MVD^e		GPI^f
					DOR/MOR	KOR/MOR
Oxymorphone	H, H, H	0.97	80.5	61.6	83	63		0.4	ND
1	Me, H, H	0.10	4.80	10.2	48	102		331	156
13	Me, Me, H	0.15	13.3	25.2	89	168		202	52
14	Et, Me, H	0.46	12.2^c	43.2	26	94		ND	49^g
15	Me, Bz, H	0.31	13.1	22.8	42	73		ND	ND
18	Bz, Me, H	0.18	3.67	2.46	20	14		696	167
20	PhPr, Me, Me	0.62	6.33	25.0	10	40		ND	ND
21	PhPr, Me, H	0.20	0.14	0.40	0.7	2		ND	ND

Bz: benzyl; Et: ethyl; Me: methyl; PhPr: phenylpropyl; K_i: inhibition constant; ND: not determined.
^aBinding against [3H]DAMGO in rat brain membranes [13, 14, 22, 23, 25, 26].
^bBinding against [3H][Ile^5,6]deltorphin II or ^c[3H]DSLET in rat brain membranes [13, 14, 22, 23, 25, 26].
^dBinding against [3H]U69,593 in rat or guinea pig brain membranes [13, 14, 22, 23, 25, 26].
^eDetermined in the MVD [13, 23, 24].
^fDetermined in the GPI [13, 23].
^gRelative to normorphine [25].
^hDetermined in the hot-plate test in mice after s.c. administration [12–14, 22].
ⁱDetermined in the tail-flick test in mice after s.c. administration [14, 22, 24].
^jDetermined in the writhing test in mice after s.c. administration [20, 22, 25].