Pharmacological characterization of a novel brain receptor recognized by a (-)-trans-1-phenyl-3-aminotetralin

Sigma receptors in mammalian forebrain are linked to modulation of dopaminergic neurotransmission in mammalian forebrain. A novel series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs), structurally related to (+)-benzomorphan sigma ligands, was designed and evaluated as potential sigma receptor ligands and for sigma receptor-mediated effects on dopamine synthesis. Two phenyl-aminotetralins, ({dollar}pm{dollar})-trans-Cl,OH-PAT and ({dollar}pm{dollar})-trans-{dollar}Hsb2{dollar}-PAT, stimulated brain dopamine synthesis in a manner similar to that of (+)-benzomorphans. The piperazine butanol sigma antagonist, BMY-14802, blocked the stimulation suggesting that the functional effects were due to interaction with a sigma receptor. Further studies, however, revealed that PATs have low affinity for known sigma {dollar}sigmasb1/sigmasb2{dollar} binding sites. Characterization (including ligand binding and brain receptor mapping studies) of sites labeled with ({dollar}sp3{dollar}H) - ({dollar}pm{dollar})-trans-Cl,OH-PAT indicated that the observed functional effects may be mediated by a site distinct from known sigma receptors. Results of these studies suggested that ({dollar}sp3{dollar}H) -PAT sites, though pharmacologically distinct from known sigma {dollar}sigmasb1{dollar} and {dollar}sigmasb2{dollar} receptors, have sigma-like characteristics, including (1) similar rank order of sigma ligand binding, (2) similar brain distribution, and (3) similar effects on brain dopamine synthesis. It was hypothesized, therefore, that phenylaminotetralins may mediate their effects on brain dopamine synthesis by interaction with a previously unidentified sigma receptor subtype, termed PAT ({dollar}sigmasb3).{dollar} The pharmacology of the proposed PAT ({dollar}sigmasb3{dollar}) site was probed further with ({dollar}sp3{dollar}H) -({dollar}-{dollar})-trans-H{dollar}sb2{dollar}-PAT, the enantiomer associated with functional effects on dopamine synthesis and higher affinity for ({dollar}sp3{dollar}H) -PAT sites. Extensive evaluation of the pharmacological profile of the proposed PAT ({dollar}sigmasb3{dollar}) site revealed that (1) a number of histamine H{dollar}sb1{dollar} receptor ligands bind with high affinity to ({dollar}sp3{dollar}H) -({dollar}-{dollar})-trans-H{dollar}sb2{dollar}-PAT sites, (2) ({dollar}pm{dollar})-trans-Cl,OH- and ({dollar}pm{dollar})-trans-H{dollar}sb2{dollar}-PAT have high affinity for H{dollar}sb1{dollar} receptors, and (3) the brain distribution of ({dollar}sp3{dollar}H) -PAT sites and H{dollar}sb1{dollar} receptors is similar. Studies to evaluate the histamine H{dollar}sb1{dollar}-nature of ({dollar}sp3{dollar}H) -({dollar}-{dollar})-trans-H{dollar}sb2{dollar}-PAT sites revealed that the rank order of ligand binding (including PATs and non-PATs) and the brain distribution of ({dollar}sp3{dollar}H) -({dollar}-{dollar})-trans-H{dollar}sb2{dollar}-PAT sites is similar but not identical to that of histamine H{dollar}sb1{dollar} receptors. Moreover, H{dollar}sb1{dollar} agonists have no effect on in vitro tyrosine hydroxylase activity in mammalian brain. Based upon these observations, it is hypothesized that ({dollar}sp3{dollar}H) -({dollar}-{dollar})-trans-H{dollar}sb2{dollar}-PAT recognizes a previously unidentified histamine Hl receptor subtype, termed H{dollar}sb{lcub}1x{rcub},{dollar} that may be linked to stimulation of dopamine synthesis in mammalian brain. Characterization of the H{dollar}sb{lcub}1x{rcub}{dollar} site may clarify the functional role of histamine as a neurotransmitter. In addition, the results of these studies may contribute to understanding the neurobiology of central sigma and histamine receptors as well as the etiology of disorders of dopamine neurotransmission, including Parkinson's disease and schizophrenia.