Histamine activates H1 G protein-coupled receptors (GPCRs) to trigger Gq activation that stimulates phospholipase (PL) C to form diacylglycerol and inositol phosphates (IP) second messengers. Brain H1 receptors also can stimulate adenylyl cyclase (AC) and formation of cAMP, leading to activation of tyrosine hydroxylase and catecholamine neurotransmitter synthesis. The pharmacotherapeutic potential of brain-penetrating H1 agonists in neuropsychiatric and neurodegenerative disorders recently became obvious when our lab reported that histamine and the novel H1 agonist 1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT) can stimulate mammalian forebrain catecholamine neurotransmitter synthesis in vivo. We designed and synthesized a series of (+/-)-2-dimethylamino- 5- and 6- (m-substituted)-phenyl-1,2,3,4-tetrahydronaphthalene derivatives (5- and 6-APTs) that represent a hybrid structure of the molecular scaffolds of PAT and 2-phenylhistamine-type H1 agonists. The synthetic route for 5-APTs proceeded via Suzuki-Miyaura palladium catalyzed cross-coupling of 5-bromo-1-tetralone with the appropriate phenylboronic acid (PBA) to give the key 5-(m-substituted)-phenyl-1-tetralone intermediates that were transposed to 2-tetralones followed by reductive amination. A similar coupling reaction was performed with ethyl 4-bromophenylacetate and the appropriate PBA to give the corresponding biphenylacetates. Ring closure to the 6-(m-substituted)-phenyl-2-tetralones, followed by reductive amination gave the 6-APTs. Affinity (Ki, uM) of compounds for human H1 receptors expressed in CHO (CHO-H1) cells: histamine (14), 5-APT (3), m-CF3, Cl, or OCH3-5-APT (3-6), 6-APT (10), m-CF3, Cl, or OCH3-6-APT (1-3), m-Br-6-APT (0.1). Histamine stimulated PLC/IP formation in CHO-H1 cells with EC50~3 uM. The 5- and 6-APTs did not significantly stimulate PLC/IP formation at concentrations near their H1 receptor Ki values; similar results are apparent for H1/AC/cAMPsignaling. Interestingly, Br-6-APT was identified as a novel competitive H1/PLC/IP antagonist. Meanwhile, H1 receptors are phylogenetically closely related to serotonin 5HT2C GPCRs, which also are implicated in treatment of neuropsychiatric disorders. Several 5- and 6-APTs were shown to be novel 5HT2C agonists that stimulate 5HT2C/PLC/IP signaling, making them attractive pharmacotherapeutic leads. Support: MH068655 and NO2MH80002.
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