Novel naphthyloxy derivatives - Potent histamine H3 receptor ligands. Synthesis and pharmacological evaluation.

摘要: Abstract A series of 1- and 2-naphthyloxy derivatives were synthesized evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed affinity the a value 21.9 nM. antagonist behaviour 11 was confirmed both in vitro cAMP assay (IC50 = 312 nM) vivo rat dipsogenia model (ED50 = 3.68 nM). Moreover, compound positive effects on scopolamine induced-memory deficits mice (at doses 10 15 mg/kg) an analgesic effect formalin test ED50 = 30.6 mg/kg (early phase) ED50 = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Ki = 53.9 nM), accepted Anticonvulsant Screening Program at National Institute Neurological Disorders Stroke/National Health (Rockville, USA). screening performed maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) 6-Hz psychomotor animal models epilepsy. Neurologic deficit by rotarod test. Compound 13 inhibited convulsions induced MES ED50 19.2 mg/kg (mice, i.p.), 17.8 (rats, 78.1 p.o.). protection against seizures (32 mA) (i.p.) 33.1 mg/kg (44 mA) 57.2 mg/kg. Furthermore, weak influence viability tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), inhibition CYP3A4 activity, no mutagenicity. Thus, these may be used as leads further search ligands promising activity.