CHARACTERIZATION OF THE AMINOMETHYLCHROMAN DERIVATIVE BAY-X-3702 AS AHIGHLY POTENT 5-HYDROXYTRYPTAMINE(1A) RECEPTOR AGONIST

The aminomethylchroman derivative BAY x 3702 hyl)-amino]-butyl)-1,1-di oxo-benzo[d]isothiazolone hydrochloride) is a new high affinity 5-hydr oxytryptamine (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-HT1A recep tors: 0.25 and 0.4 nM, respectively]. BAY x 3702 bound also with relat ively high to moderate affinity to the following receptors: alpha-1 an d alpha-2 adrenergic (K-i: 6 and 7 nM, respectively); 5-HT7- and 5-HT1 D (7 and 36 nM); dopamine D-2- and D-4 (48 and 91 nM); sigma sites (17 6 nM) and 5-HT2C (310 nM); others: > 10 mu M, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cy clase assay in rat hippocampal tissue, a model of postsynaptic 5-HT1A receptor function, BAY x 3702 was a potent 5-HT1A receptor full agonis t (IC50: 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT1A re ceptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N(2-p yridinyl)cyclohexane carboxamide trihydrochloride (WAY-100635). At tho se receptors where BAY x 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT1D 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-HT1A receptor function, BAY x 3702 inhibited potently (1 nM) neurona l firing. Also in vivo, BAY x 3702 (0.5 mu g/kg, i.v,) was found to su ppress 5-HT neuronal firing in the DRN of anesthetized rats. in both e lectrophysiological assays BAY x 3702 was more potent than 3-OH-DPAT a nd ipsapirone; the potency difference being about 1 and 2 orders of ma gnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalizati on was obtained with BAY x 3702 (ED50 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 x 3702 induced a WAY-100635-reversi ble effect and the compound had a higher potency and intrinsic activit y than 8-OH-DPAT and ipsapirone (ED50: 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 x 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapiron e (ED50: 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY x 3702 is a relatively selective 5-HT1A receptor agonist with hig h potency and intrinsic activity.