SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 1-PHENYL-3-AMINO-1,2,3,4-TETRAHYDRONAPHTHALENES AS LIGANDS FOR A NOVEL RECEPTOR WITH SIGMA-LIKENEUROMODULATORY ACTIVITY
Sd. Wyrick et al., SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 1-PHENYL-3-AMINO-1,2,3,4-TETRAHYDRONAPHTHALENES AS LIGANDS FOR A NOVEL RECEPTOR WITH SIGMA-LIKENEUROMODULATORY ACTIVITY, Journal of medicinal chemistry, 36(17), 1993, pp. 2542-2551
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.