Design, synthesis, and structure-activity relationships of acetylene-basedhistamine H-3 receptor antagonists

New, potent, and selective histamine H-3 receptor antagonists have been syn thesized by employing the use of (1) an appropriately positioned nonpolar a cetylene spacer group, (2) either a two-carbon straight chain linker or a c onformationally restricting trans-cyclopropane ring between the C-4 positio n of an imidazole headgroup and the acetylene spacer, and (3) a Topliss ope rational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straigh t chain linker, whereas 26-31 are analogues prepared by incorporation of th e trans-(+/-)-cyclopropane at the C-4 position of an imidazole headgroup. S ynthesis of both the (1R,2R)- and (1S,2S)-cyclopropyl enantiomers of the mo st potent racemic compound 31 (K-i = 0.33 +/- 0.13 nM) demonstrated a stere opreference in H-3 receptor binding affinity for the (1R,2R) enantiomer 32 (K-i = 0.18 +/- 0.04 nM) versus the (1S,2S) enantiomer 33 (K-i = 5.3 +/- 0. 5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)- imidazole (32) is one of the most potent histamine H-3 receptor antagonists reported to date .