Effect of structural modification in the amine portion of substituted aminobutyl-benzamides as ligands for binding σ1 and σ2 receptors

Abstract

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide (1) is one of the most potent and selective σ2 receptor ligands reported to date. A series of new analogs, where the amine ring fused to the aromatic ring was varied in size (5 - 7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their σ1 / σ2 binding affinity and selectivity. The binding affinity of an open-chained variant of 1 was also evaluated. Only the 5-membered ring congener of 1 displayed a higher σ1 / σ2 selectivity, derived from a higher σ2 affinity and a lower σ1 affinity. Positioning the nitrogen adjacent to the aromatic ring in the 5-membered and 6-membered ring congeners dramatically decreased affinity for both subtypes. Thus, location of the nitrogen within a constrained ring is confirmed to be key to the exceptional σ2 receptor binding affinity and selectivity for this active series.

Classes of Sigma2 (σ2) Receptor Ligands: Structure Affinity Relationship (SAfiR) Studies and Antiproliferative Activity

“…Highly 2 selective granatane derivatives with -Aminoalkyl side chains (See [33] varied from the position held in the tetrahydroisoquinoline ring: all the possible cyclo-isomers in the five, six and seven member rings were built, and a reduction of 2 affinity was found for all isomers, with a dramatic drop when the N-atom was directly attached to the benzene ring, maybe for a reduced basic character Fig. (17) [39].…”

“…Thus, the effect of the conformational freedom of the 6,7-dimethoxytetrahydroiso-quinoline on receptor interactions was studied. Five-membered and seven-membered rings containing the N-atom were fused to the benzene ring mimicking the 6,7-dimethoxytetrahydroisoquinoline structure respectively in a more or less constrained structure [39]. The five-membered fused ring provided a 10-fold higher 2 affinity than the tetrahydroisoquinoline lead compound 9.…”

“…. Schematic SAfiR from 6,7-dimethoxytetrahydroisoquinoline modifications (See[39] for binding protocol).…”

Tactics for preclinical validation of receptor-binding radiotracers

“…Both test ligand and radioligand solutions should be checked for stability during the course of the experiments. HPLC is a helpful tool to analyze their concentration and purity when indicated [46,92]. …”

The σ2 Receptor: A Novel Protein for the Imaging and Treatment of Cancer

“…68 An exception to this trend was compound 35 , the 5-membered ring congener of 23 , which showed high affinity and selectivity for σ 2 receptors. 68 Finally, the tri-methoxy benzamide analog in which the 6,7-dimethoxy group of the tetrahydroisoquinoline ring was replaced with a 7-nitro group to give compound 36 was found to have good selectivity but modest affinity for the σ 2 receptor. 69 …”