Probes for Narcotic Receptor-Mediated Phenomena. 25. Synthesis and Evaluation ofN-Alkyl-Substituted (α-Piperazinylbenzyl)benzamides as Novel, Highly Selective δ Opioid Receptor Agonists

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Abstract
A series of N-alkyl- and N,N-dialkyl-4-[α-{(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl}benzyl]benzamides were synthesized and evaluated for binding affinities at μ, δ, and κ opioid receptor subtypes. Several compounds (2e,f,h,i,m) strongly bound to the δ receptor with IC50 values in the nanomolar range. On the other hand, the binding affinities of these compounds for the μ and κ receptors were in the micromolar or greater range indicating excellent δ opioid receptor subtype selectivities. In this series, two important structure−activity relationships were found for the δ receptor binding affinity. First, the spatial orientation of the α-benzylic position influenced the affinities with the αR derivatives 2a−n generally showing more than 10-fold greater affinity than the αS derivatives 3a−n. Second, the binding affinities were strongly influenced by the number of alkyl substituents on the amide nitrogen. N-Monoalkylbenzamide derivatives 2b−d showed lower affinity than N,N-dialkylbenzamide derivatives 2e−n, and the N-unsubstituted benzamide derivative 2a had the lowest affinity for the δ receptor in the series. The dramatic effect of the amide group substitution pattern on the binding affinity for the δ receptor strongly suggests that the amide function is an important structural element in the interaction of this series of compounds at the δ receptor. Selective compounds in this series were examined for binding affinity in cloned human μ and δ receptors. The results obtained generally paralleled those from the rat brain binding assay. Compounds 2e,f with potent δ binding affinities and high δ selectivities were shown to be δ agonists with high selectivity by studies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Compound 2f was the most selective compound in the rat brain and GPI/MVD assays with 1755- and 958-fold δ vs μ selectivity, respectively.