title: Synthesis and evaluation of optically pure [3H]-(+)-pentazocine, a highly potent and selective radioligand for sigma receptors.
abstract: Tritium-labeled (+)-pentazocine ([3H]-1b) of specific activity 26.6 Ci/mmol was synthesized in 3 steps starting with (+)-normetazocine (2) of defined optical purity. [3H]-1b has been characterized as a highly selective ligand for labeling of sigma receptors. Competition data revealed that [3H]-1b could be displaced from guinea pig brain membrane preparations with a number of commonly used sigma receptor ligands. [3H]-1b exhibited saturable, enantioselective binding with a Kd of 5.13 +/- 0.97 nM and a Bmax of 1146 +/- 122 fmol/mg protein. Phencyclidine (PCP) displaced [3H]-1b with low affinity while MK-801 was inactive, thus indicating insignificant activity at the PCP-binding site; apomorphine failed to displace [3H]-1b indicating lack of dopamine receptor cross-reactivity. Since the affinity of [3H]-1b is about 6 times that of the two commonly employed sigma ligands ((+)-3-[3H]PPP and [3H]DTG) and since it is more selective for sigma receptors than the benzomorphan [3H]SKF-10,047, it represents the first example of a highly selective benzomorphan based sigma receptor ligand. [3H]-1b should prove useful for further study of the structure and function of sigma receptors.
authors.affiliation: Laboratory of Medicinal Chemistry, National Institute of Digestive, Diabetes, and Kidney Diseases, Bethesda, MD 20892.
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
authors.forename: S B
authors.initials: SB
authors.lastname: Hellewell
authors.forename: J M
authors.initials: JM
authors.lastname: Walker
authors.forename: A
authors.initials: A
authors.lastname: Thurkauf
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D015259:Dopamine Agents; D006146:Guanidines / Q000378:metabolism; D006168:Guinea Pigs; D006878:Hydroxides; D015394:Molecular Structure; D010423:Pentazocine / Q000138:chemical synthesis* / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011188:Potassium; D017680:Potassium Compounds; D011954:Receptors, Dopamine / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017480:Receptors, sigma; D014316:Tritium
chemical_list: D015259:Dopamine Agents; D006146:Guanidines; D006878:Hydroxides; D010880:Piperidines; D017680:Potassium Compounds; D011954:Receptors, Dopamine; D011957:Receptors, Opioid; D017480:Receptors, sigma; D014316:Tritium; C026539:preclamol; D010622:Phencyclidine; C050232:1,3-ditolylguanidine; D001058:Apomorphine; D010423:Pentazocine; D011188:Potassium; C029943:potassium hydroxide