1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and Related Derivatives as Ligands for the Neuromodulatory σ₃ Receptor: Further Structure-Activity Relationships

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 σ₃ receptor. Specifically, the trans-1R,3S-(-) isomer of H₂-PAT showed highest affinity for σ₃ receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for σ₃ 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 σ₃ 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-(trimethylam-moniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased σ₃ receptor affinity and, in some cases, caused a reversal of the σ₃ binding selectivity of transversus cis-PATs found previously. Most analogs were selective for σ₃ receptors and showed little or no affinity for either σ₁\σ₂ or dopamine D₁, D₂, and D₃ receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced σ₁/σ₂ and dopamine receptor affinity while decreasing σ₃ affinity, thus abolishing σ₃ selectivity.