1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and related derivatives as ligands for the neuromodulatory sigma 3 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 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.
Wyrick
S D
SD
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Booth
R G
RG
Myers
A M
AM
Owens
C E
CE
Bucholtz
E C
EC
Hooper
P C
PC
Kula
N S
NS
Baldessarini
R J
RJ
Mailman
R B
RB
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001549:Benzamides; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes; D014446:Tyrosine 3-Monooxygenase; C030265:nemonapride