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 af finity 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'-(-)-Iodopentazo cine competes at sigma(1) receptor binding sites with a K-i value of 8 nM, compared to approximately 40 nM for(-)-pentazocine. 3'-(-)-Iodope ntazocine also has lost its affinity for opioid receptors. In contrast , iodination of(+)-pentazocine lowers its affinity at sigma(1) recepto rs. Synthesis of [I-125]3'-(-)-iodopentazocine is readily performed wi th 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 ultr aviolet light can covalently couple the ligand into the membranes. Pol yacrylamide gel electrophoresis reveals a major band at about 25 kDa a nd a minor one at about 20 kDa, indicating photolabeling of sigma(1) r eceptors with minor incorporation into sigma(2) sites.