Synthesis and characterization of [I-125]3'-(-)-iodopentazocine, a selective sigma(1) receptor ligand

Pentazocine is a potent ligand at both opioid and sigma receptors, but with opposite stereoselectivities. Whereas(-)-pentazocine has high affinity for a number of opioid receptors, (+)-pentazocine labels sigma(1) receptors. Iodination of(-)-pentazocine at the 3'-position reverses its selectivity for opioid and sigma(1) receptors. 3'-(-)-Iodopentazocine competes at sigma(1) receptor binding sites with a K-i value of 8 nM, compared to approximately 40 nM for(-)-pentazocine. 3'-(-)-Iodopentazocine also has lost its affinity for opioid receptors. In contrast, iodination of(+)-pentazocine lowers its affinity at sigma(1) receptors. Synthesis of [I-125]3'-(-)-iodopentazocine is readily performed with incorporations of up to 80%. Binding is of high affinity and shows the selectivity anticipated for a sigma(1) receptor-selective ligand. Exposing membranes prebound with [I-125]3'-(-)-iodopentazocine to ultraviolet light can covalently couple the ligand into the membranes. Polyacrylamide gel electrophoresis reveals a major band at about 25 kDa and a minor one at about 20 kDa, indicating photolabeling of sigma(1) receptors with minor incorporation into sigma(2) sites.