Structure-affinity-relationship study of bicyclic sigma receptor ligands

It was postulated that N(6)-allyl bicyclic derivatives 1 bind with N-8 at the proton donor site of the sigma(1) receptor and that a substituent in 2-position of the bicyclic framework 1 results in unfavorable steric interactions with the sigma(1) receptor protein. In order to support this hypothesis both enantiomers of 6-allyl-8-(4-methoxybenzyl)-6,8-diazabi-cyclo[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 sigma(1) pharmacophore model. The N(6)-allyl derivative 2 with a double bond in the three carbon bridge adopts the orientation 2c with N-8 interacting with the sigma(1) receptor proton donor site (Fig. 2) resulting in slightly reduced steric interactions of the small double bond in 2/3-position. The almost C(2)-symmetric benzyl derivative 3 can adopt both orientations 2c and 2d at the sigma (1) receptor (N-8 or N-6 interacts with the sigma (1) receptor proton donor site) resulting in subnanomolar sigma(1) receptor affinity (K(i) = 0.91 nM).