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 (Ki = 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 (Ki = 105 nM). Unlike its potent σ activity, the compound has little affinity for dopamine D1 (Ki = 2.9 μM), D2 (Ki = 2.35 μM), muscarinic M1 (Ki = 0.88 μM) or M2 (Ki = 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.
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