RLH-033, a novel, potent and selective ligand for the σ₁ recognition site

RLH-033 [2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)cyclopentanecarboxylate HCl] is a rationally designed ligand that was synthesized and evaluated for its binding affinities at σ₁ and σ₂ sites in guinea pig brain. RLH-033 has high affinity (K_i = 50 pM) for σ₁ sites labeled by [³H](+)-pentazocine, while it has over 2000-fold less affinity at σ₂ sites labeled by [³H]1,3-di(2-tolyl)guanidine (DTG) in the presence of 500 nM (+)-pentazocine (K_i = 105 nM). Unlike its potent σ activity, the compound has little affinity for dopamine D₁ (K_i = 2.9 μM), D₂ (K_i = 2.35 μM), muscarinic M₁ (K_i = 0.88 μM) or M₂ (K_i = 1.7 μM) receptors, and none at all for N-methyl-D-aspartate, phencyclidine and opioid receptors. Thus, RLH-033 is the most potent σ₁ ligand reported to date, and its very high affinity suggests it may be a useful radioligand to characterize the pharmacology of σ₁ recognition sites.