SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 1-PHENYL-3-AMINO-1,2,3,4-TETRAHYDRONAPHTHALENES AS LIGANDS FOR A NOVEL RECEPTOR WITH SIGMA-LIKENEUROMODULATORY ACTIVITY

Certain novel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-pheny l-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal le vels) of tyrosine hydroxylase (TH) activity at 0.1 muM concentrations in rodent brain tissue. This effect on TH was blocked by the putative sigma-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory sigma-like receptor. Within the new phenylaminotetral in series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by )-6-chloro-7- hydroxy-1,2,3,4-tetrahydronaphthalene {[H-3](+/-)-4}. trans-Catechol a nalogs had low affinity for [H-3]4 sites, and although they inhibited TH activity, this effect was not blocked by known sigma or dopamine an tagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [H- 3]4 binding sites and did not significantly affect TH activity. The ph armacology of the [H-3]4 binding site is unique from that of any known sigma or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has ster eoselectivity for the (1R,3S)-(-)-isomer of (N,N-dimethylamino)-1,2,3, 4-tetrahydronaphthalene; this isomer is also more active at stimulatin g TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes ap pear to be selective probes of a novel receptor type that mediates cr- like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.