Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist.

The aminomethylchroman derivative BAY × 3702 (R-(−)-2-{4-[(chroman-2-ylmethyl)-amino]-butyl}-1,1-dioxo-benzo[d]isothiazolone hydrochloride) is a new high affinity 5-hydroxytryptamine (5-HT) 1A receptor ligand [calf hippocampus: K i : 0.19 nM; reference compounds 8-hydroxy-2-(di- n -propylamino)-tetralin (8-OH-DPAT) and ipsapirone: 0.98 and 2.56, respectively; rat cortex: 0.24 nM; rat hippocampus: 0.58 nM; human cortex and recombinant 5-HT 1A receptors: 0.25 and 0.4 nM, respectively]. BAY × 3702 bound also with relatively high to moderate affinity to the following receptors: alpha -1 and alpha -2 adrenergic ( K i : 6 and 7 nM, respectively); 5-HT 7 − and 5-HT 1D (7 and 36 nM); dopamine D 2 − and D 4 (48 and 91 nM); sigma sites (176 nM) and 5-HT 2C (310 nM); others: >10 μM, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cyclase assay in rat hippocampal tissue, a model of postsynaptic 5-HT 1A receptor function, BAY × 3702 was a potent 5-HT 1A receptor full agonist (IC 50 : 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY-100635). At those receptors where BAY × 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT 1D receptors) or an antagonist ( alpha -1, alpha -2 and D 2 receptors). In a rat brain slice preparation containing the dorsal raphe nucleus (DRN), a model of somatodendritic 5-HT 1A receptor function, BAY × 3702 inhibited potently (1 nM) neuronal firing. Also in vivo, BAY × 3702 (0.5 μg/kg, i.v.) was found to suppress 5-HT neuronal firing in the DRN of anesthetized rats. In both electrophysiological assays BAY × 3702 was more potent than 8-OH-DPAT and ipsapirone; the potency difference being about 1 and 2 orders of magnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalization was obtained with BAY × 3702 (ED 50 : 0.022 mg/kg, i.p. and 0.38 mg/kg, p.o.; 8-OH-DPAT: 0.028 mg/kg, i.p. and ipsapirone: 0.44 mg/kg, i.p.). In the rat hypothermia model BAY × 3702 induced a WAY-100635-reversible effect and the compound had a higher potency and intrinsic activity than 8-OH-DPAT and ipsapirone (ED 50 : 0.25 mg/kg, i.p. and 5.4 mg/kg, p.o., respectively; 8-OH-DPAT: 1.1 mg/kg, i.p. and ipsapirone: 6.2 mg/kg, i.p.). BAY × 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapirone (ED 50 : 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY × 3702 is a relatively selective 5-HT 1A receptor agonist with high potency and intrinsic activity.