NEW SIGMA-LIKE RECEPTOR RECOGNIZED BY NOVEL PHENYLAMINOTETRALINS - LIGAND-BINDING AND FUNCTIONAL-STUDIES

Several novel phenylaminotetralins (PATs) cause functional changes in brain that are associated with binding to saturable, high affinity sit es that are not identical to any known central nervous system receptor . These PATs were tested for their ability to cause receptor-mediated functional effects on tyrosine hydroxylase activity in corpus striatum from rat and guinea pig brain. o-6-chloro-7-hydroxy-1,2,3,4-tetrahydr onaphthalene (Cl,OH-PAT) increased tyrosine hydroxylase activity (by a pproximately 30-40%) at 0.1 mum. Higher concentrations inhibited enzym e activity by indirect mechanisms that may include displacement of int raneuronal dopamine. The 6,7-unsubstituted congener nyl-3-di-methylami no-1,2,3,4-tetrahydronaphthalene stimulated tyrosine hydroxylase by as much as 50-60% over basal activity, without displacement of dopamine. Similarly to certain (+)-benzomorphan sigma receptor ligands, the eff ects of both PATs to activate tyrosine hydroxylase were blocked compet itively by the putative sigma antagonist BMY-14802. Radiolabeled [H-3] Cl,OH-PAT bound saturably and with high affinity to guinea pig brain m embranes (K(d) = 31 pm, B(max) = 6.5 fmol/mg of protein). The pharmaco logical profile of these binding sites was inconsistent with those of known sigma1, sigma2, dopaminergic, serotonergic, adrenergic, opioid, N-methyl-D-aspartate, or several other characterized central nervous s ystem recognition sites. Together, these data suggest that these PATs may be agonists at a novel sigma-like site that has neuromodulatory ac tivity that results in increases of brain catecholamine synthesis via activation of tyrosine hydroxylase.