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 sites 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. (+/-)-(trans)-1-Phenyl-3-dimethylamino-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene (CI, OH-PAT) increased tyrosine hydroxylase activity (by approximately 30-40%) at 0.1 microM. Higher concentrations inhibited enzyme activity by indirect mechanisms that may include displacement of intraneuronal dopamine. The 6,7-unsubstituted congener (+/-)-(trans)-1-phenyl-3-dimethylamino-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 effects of both PATs to activate tyrosine hydroxylase were blocked competitively by the putative sigma antagonist BMY-14802. Radiolabeled [3H]CI,OH-PAT bound saturably and with high affinity to guinea pig brain membranes (Kd = 31 pm, Bmax = 6.5 fmol/mg of protein). The pharmacological profile of these binding sites was inconsistent with those of known sigma 1, sigma 2, dopaminergic, serotonergic, adrenergic, opioid, N-methyl-D-aspartate, or several other characterized central nervous system recognition sites. Together, these data suggest that these PATs may be agonists at a novel sigma-like site that has neuromodulatory activity that results in increases of brain catecholamine synthesis via activation of tyrosine hydroxylase.