Structure-Affinity-Relationship Study of Bicyclic σ Receptor Ligands

Ralph      Holl; Christian      Geiger; Masakazu      Nambo; Kenichiro      Itami; Dirk      Schepmann; Bernhard      Wunsch

doi:10.2174/1871524910909030220

Abstract

It was postulated that N6-allyl bicyclic derivatives 1 bind with N-8 at the proton donor site of the σ1 receptor and that a substituent in 2-position of the bicyclic framework 1 results in unfavorable steric interactions with the σ1 receptor protein. In order to support this hypothesis both enantiomers of 6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[ 3.2.2]non-2-ene (2/ent-2) and 6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane 3/ent-3 were synthesized stereoselectively. The (S,S)-configured enantiomers 2 and 3 are the eutomers with eudismic ratios of 31 and 4.8, respectively. Therefore, these enantiomers are used in the σ1 pharmacophore model. The N6-allyl derivative 2 with a double bond in the three carbon bridge adopts the orientation 2c with N-8 interacting with the σ1 receptor proton donor site (Fig. 2) resulting in slightly reduced steric interactions of the small double bond in 2/3-position. The almost C2-symmetric benzyl derivative 3 can adopt both orientations 2c and 2d at the σ1 receptor (N-8 or N-6 interacts with the σ 1 receptor proton donor site) resulting in subnanomolar σ1 receptor affinity (Ki = 0.91 nM).

Keywords: ??1 receptor ligands: 6,8-diazabicyclo[3.2.2]nonanes, 6,8-diazabicyclo[3.2.2]nonenes, pharmacophore model

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