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A novel phenylaminotetralin (PAT) radioligand, [(3)H]-(1R, 3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene ([(3)H]-[-]-trans-H(2)-PAT), is shown here to label a saturable (B(max)=39+/-6 fmol/mg protein) population of sites with high affinity (K(d)=0.13+/-0.03 nM) in guinea pig brain. Consistent with previous studies which showed that PATs stimulate catecholamine (dopamine) synthesis in rat striatum, autoradiographic brain receptor mapping studies here indicate that [(3)H]-(-)-trans-H(2)-PAT-labeled sites are highly localized in catecholaminergic nerve terminal fields in hippocampus, nucleus accumbens, and striatum in guinea pig brain. Competition binding studies with a broad range of CNS receptor-active ligands and CNS radioreceptor screening assays indicate that the pharmacological binding profile of brain [(3)H]-(-)-trans-H(2)-PAT sites closely resembles histamine H(1)-type receptors. Comparative studies using the histamine H(1) antagonist radioligand, [(3)H]mepyramine, indicate that the H(1) ligand binding profile and guinea pig brain distribution of H(1) receptors and [(3)H]-(-)-trans-H(2)-PAT sites are nearly identical; moreover, both sites have about 40-fold stereoselective affinity for (-)- over (+)-trans-H(2)-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (sigma(3)) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H(1) receptors that can be stereoselectively labeled with [(3)H]-(-)-trans-H(2)-PAT., (Copyright 1999 Published by Elsevier Science B.V.)

A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel sigma 3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for sigma 3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for sigma 3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the sigma 3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylammoniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased sigma 3 receptor affinity and, in some cases, caused a reversal of the sigma 3 binding selectivity of trans- versus cis-PATs found previously. Most analogs were selective for sigma 3 receptors and showed little or no affinity for either sigma 1/sigma 2 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced sigma 1/sigma 2 and dopamine receptor affinity while decreasing sigma 3 affinity, thus abolishing sigma 3 selectivity.

Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.