Antinociceptive (aminoalkyl)indoles

Abstract

The (aminoalkyl)indole (AAI) derivative pravadoline (1a) inhibited prostaglandin (PG) synthesis in mouse brain microsomes in vitro and ex vivo and exhibited antinociceptive activity in several rodent assays. In vitro structure-activity relationship studies of this new class of PG synthesis inhibitors revealed a correspondence in three respects to those reported for the arylacetic acids: (1) "alpha-methylation" caused an increase in PG inhibitory potency, (2) the (R)-alpha-methyl isomer was more active than the S isomer, (3) the hypothesized aroyl group conformation of the 2-methyl derivatives corresponded to the proposed and reported "active" conformations of the aroyl and related aromatic acetic acid derivatives. The 1H NMR chemical shift of the C-4 hydrogen of pravadoline in comparison to the deshielding seen with 50, which lacks a substituent at C-2, suggested that the carbonyl group of pravadoline is located near C-2 but is located near C-4 in 50. Associated with this conformational change of the carbonyl group of 1a is a diminution of PG synthetase inhibitory activity. The results of UV and difference nuclear Overhauser studies of the two compounds were consistent with these conformational assignments. The low eudismic ratios of the alpha-methyl derivatives and the observation that the side chain may be extended by three methylene groups without significant loss of PG inhibitory potency suggests that this class of inhibitors bound less strongly and less selectively to the active site of PG synthetase than do the arylacetic acids. Two AAIs, 1a and 30, were found to be metabolized to the corresponding acetic acid derivatives, both of which inhibited PG synthesis. An exception to the observation that the antinociceptive activity of the AAIs was associated with PG synthetase inhibitory activity was the 1-naphthoyl derivative 67 since neither it nor its acetic acid metabolite 74 inhibited PG synthesis. Yet 67 was antinociceptive in four different rodent assays. This naphthoyl derivative, like opioids, also inhibited electrically stimulated contractions in the mouse vas deferens (MVD) preparation. Unlike opioids, however, the inhibition was not antagonized by naloxone. A subseries of AAIs was identified, of which 67 was prototypic. These compounds lacked PG synthetase inhibitory activity, but their inhibitory potency in MVD preparations correlated roughly with their antinociceptive potency in vivo. Pravadoline was also inhibitory in the MVD. Its antinociceptive activity, therefore, may be a consequence of both its PG synthetase inhibitory potency and another antinociceptive mechanism, the latter associated with its inhibitory potency in the MVD.(ABSTRACT TRUNCATED AT 400 WORDS)

In Vitro Metabolism of R(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist

“…2 ) are a structurally distinct group of cannabinoid receptor agonists that were originally developed from pravadoline Bell et al, 1991;D'Ambra et al, 1992;Kuster et al, 1992;Eissenstat et al, 1995). AAIs have been found to displace potent cannabinoid ligands such as CP-55940 in competitive binding to the CB1 cannabinoid receptor .…”

Cannabinoid‐receptor expression in human leukocytes

“…The concentration of dimethylsulfoxide in the assays never exceeded 1 %, a concentration which was without effect on radioligand binding. The aminoalkylindole analogue WIN 55225 [( 1 -(2-morpholin-4-yl-ethyl)-1H-indol-3-yl)naphtalen-l -yl-methanone] was synthesized at the chemistry department, Sanofi Recherche (Montpellier, France) as described (Bell et al, 1991).…”

In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

“…The role of CB 2 in mediating physiological effects has not been fully determined, but it is believed that CB 2 may be involved in cannabinoid-mediated immune responses (Bouaboula et al, 1999;Portier et al, 1999). A large variety of compounds have been found to bind to the receptors, including natural and synthetic cannabinoids (Razdan, 1986;Keimowitz et al, 2000), aminoalkylindoles (Bell et al, 1991;Shim et al, 1998), endogenous ligands, and diarylpyrazoles (Compton et al, 1993;Wiley et al, 2001).…”