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

Table 2

Comparison of pharmacological and physicochemical properties of morphine, 14-O-methyloxymorphone (1), 14-methoxymetopon (13), and its 5-benzyl-substituted analogue 15.

	Agonist activity^a	Antinociception	Motor coordination^d	Log P ^g
	[^35S]GTPγS (EC50, nM; % stim)	ED50 (mg/kg)
Morphine	462; 85	2.63^b; 2.29^c	10^e	0.88
1	23.7; 108	0.017^b; 0.014^c	0.06^e	0.60
13	63.0; 110	0.028^b; 0.028^c	0.1^e	1.12
15	13.7; 85	0.053^b; 0.043^c	0.2^f	1.49

EC₅₀: effective concentration necessary to produce a 50% effect; ED₅₀: effective analgesic dose to produce a 50% effect; log P: partition coefficient.
^aDetermined in [³⁵S]GTPγS functional assays in rat brain membranes; Data as % stimulation relative to DAMGO [14].
^bDetermined in the hot-plate test in mice after s.c. administration [14].
^cDetermined in the tail-flick test in mice after s.c. administration [14].
^dDetermined in the rotarod test in mice after s.c. administration [14].
^eSignificant decrease [14].
^fNo significant effect [14].
^gThe experimental log P determined in octanol/water [14].