RLH-033, a novel, potent and selective ligand for the sigma 1 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 sigma 1 and sigma 2 sites in guinea pig brain. RLH-033 has high affinity (Ki = 50 pM) for sigma 1 sites labeled by [3H](+)-pentazocine, while it was over 2000-fold less affinity at sigma 2 sites labeled by [3H]1,3-di(2-tolyl)guanidine (DTG) in the presence of 500 nM (+)-pentazocine (Ki = 105 nM). Unlike its potent sigma activity, the compound has little affinity for dopamine D1 (Ki = 2.9 microM), D2 (Ki = 0.35 microM), muscarinic M1 (Ki = 0.88 microM) or M2 (Ki = 1.7 microM) receptors, and none at all for N-methyl-D-aspartate, phencyclidine and opioid receptors. Thus, RLH-033 is the most potent sigma 1 ligand reported to date, and its very high affinity suggests it may be a useful radioligand to characterize the pharmacology of sigma 1 recognition sites.
Hudkins
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Albany Molecular Research, NY 12203.
Mailman
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DeHaven-Hudkins
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D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010423:Pentazocine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000187:drug effects*
D000927:Anticonvulsants; D003517:Cyclopentanes; D006146:Guanidines; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; C088263:RLH 033; C050232:1,3-ditolylguanidine; D010423:Pentazocine