STUDIES ON THE PHARMACOLOGY OF THE NOVEL HISTAMINE H-3 RECEPTOR AGONIST SCH-50971

Experiments were performed to characterize the pharmacology of Sch 509 71 trans-4(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H-3 receptor agonist. The activit y of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CA S 75614-87-8), a potent and moderately selective agonist of histamine H-3 receptors, in a series of in vitro and in vivo assays. Sch 50971 i s a high affinity, selective H-3 receptor agonist in vitro and in vivo . Sch 50971 inhibits [H-3]-N-alpha-methylhistamine (CAS 67350-7) bindi ng to the histamine H-3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric f ield stimulated guinea pig ileum contractions (pD(2) = 7.47) and decre ases [H-3]-norepinephrine (CAS 51-41-2) release (pD(2) = 7.48) from gu inea pig pulmonary artery by activation of presynaptic inhibitory H-3 receptors. The in vitro effects of Sch 50971 are antagonized by low co ncentrations of a selective H-3 antagonist, thioperamide (CAS 106243-1 6-7). Sch 50971 has low affinity (IC50's > 10 mu mol/l) for histamine H-1, dopamine D-1 and D-2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H-2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H-3 agonist activ ity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/k g i.v., ED30 = 1.0 mg/kg i.d.). Sch 50971 also inhibits the effects of sympathetic nerve stimulation on nasal resistance in cats. In these a ssays, Sch 50971 exhibits an efficacy and potency comparable to H-3-ag onist (R)-alpha-methylhistamine. However, under in vivo conditions, Sc h 50971 does not exhibit histamine H-3-mediated responses that are see n with (R)-alpha-methylhistamine at Closes close to those that produce H-3 effects. Therefore, Sch 50971 is a novel, potent and selective ag onist of histamine H3 receptors with an improved in vitro and in vivo receptor profile selectivity compared with (R)-alpha-methylhistamine.