Rg. Booth et al., NEW SIGMA-LIKE RECEPTOR RECOGNIZED BY NOVEL PHENYLAMINOTETRALINS - LIGAND-BINDING AND FUNCTIONAL-STUDIES, Molecular pharmacology, 44(6), 1993, pp. 1232-1239
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.