Homologous N-alkylnorketobemidones. Correlation of receptor binding with analgesic potency

Abstract

For a homologous series of N-alkylnorketobemidones a statistically significant correlation was found between the relative abilities to bind mouse brain homogenate in vitro and their in vivo mouse hot-plate analgesic potencies. The correlation between in vitro binding in the presence of 100 mM sodium and analgesic potency was not as good AS THAT as that found in the absence of sodium. A statistically significant correlatin was found between thir analgesic potencies and their abilities to antogonize electrically induced contractions of the guinea pig ileum.

The opiate receptor: a model explaining structure-activity relationships of opiate agonists and antagonists.

“…For ketobemidones (Fig. 1), and to a lesser extent meperidine, increasing the length of the N-substituent from methyl to ethyl and propyl markedly reduces affinity for the opiate receptor and analgesic potency, while pentyl, hexyl, and heptyl substituents provide potent opiate agonists, but the octyl, nonyl, and decyl substituents result in a marked loss of activity (24). Ethyl and propyl substituents may interfere with the approach of the amine nitrogen to the anionic site of the receptor, accounting for reduced potency.…”

Interconverting mu and delta forms of the opiate receptor in rat striatal patches.

“…Later, Kosterlitz documented a dramatic difference between the ",u receptors" of the guinea pig ileum (where morphine is pharmacologically more potent than opiate peptides) and the "8 receptors" of the vas deferens (where the opposite rank order ofpotency is apparent) (3). The ,u-receptor-like rank order of potency of opiates in displacing[3H]naloxone binding from brain membranes correlates quite precisely with their ability to elicit "analgesia" in rodents (4,5) as well as to suppress guinea pig ileal contractions (6), while the 8-receptor-like rank order ofdisplacement of3H-labeled opiate peptide binding correlates with the suppression of mouse vas deferens contractions (3, 7).It has been previously reported that GTP inhibits "type 1" opiate binding, which has a ,-receptor-like ligand selectivity pattern (8, 9) and a highly discrete localization in brain when visualized autoradiographically (10). By contrast, "type 2" binding is more sensitive to displacement by peptides than by alkaloids (8, 9), has a much more diffuse brain distribution (11), and is more resistant to GTP inhibition.…”

“…[3H]naloxone binding from brain membranes correlates quite precisely with their ability to elicit "analgesia" in rodents (4,5) as well as to suppress guinea pig ileal contractions (6), while the 8-receptor-like rank order ofdisplacement of3H-labeled opiate peptide binding correlates with the suppression of mouse vas deferens contractions (3,7).…”

Inhibition of brain [3H]cimetidine binding by improgan-like antinociceptive drugs

“…For example, Compton et al (1993) demonstrated significant correlations between the cannabinoid CB 1 -receptor binding affinities and cannabinoid-like “tetrad” effects for 29 compounds. Similar studies have validated the clinical analgesic relevance of μ-opioid receptor binding assays (Wilson et al, 1975; Pert and Snyder, 1973). Presently, it was reasoned that if the [ 3 H]cimetidine-binding site represents the improgan antinociceptive receptor, then the [ 3 H]cimetidine-binding affinities for improgan-like congeners should correlate with their antinociceptive potencies.…”