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Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971.
Arzneimittelforschung. 1998 Sep; 48(9):881-8.A

Abstract

Experiments were performed to characterize the pharmacology of Sch 50971 ((+)-trans-4-(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H3 receptor agonist. The activity of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CAS 75614-87-8), a potent and moderately selective agonist of histamine H3 receptors, in a series of in vitro and in vivo assays. Sch 50971 is a high affinity, selective H3 receptor agonist in vitro and in vivo. Sch 50971 inhibits [3H]-N-alpha-methylhistamine (CAS 673-50-7) binding to the histamine H3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric field stimulated guinea pig ileum contractions (pD2 = 7.47) and decreases [3H]-norepinephrine (CAS 51-41-2) release (pD2 = 7.48) from guinea pig pulmonary artery by activation of presynaptic inhibitory H3 receptors. The in vitro effects of Sch 50971 are antagonized by low concentrations of a selective H3 antagonist, thioperamide (CAS 106243-16-7). Sch 50971 has low affinity (IC50's > 10 mumol/l) for histamine H1, dopamine D1 and D2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H3 agonist activity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/kg 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 assays, Sch 50971 exhibits an efficacy and potency comparable to H3-agonist (R)-alpha-methylhistamine. However, under in vivo conditions, Sch 50971 does not exhibit histamine H1-mediated responses that are seen with (R)-alpha-methylhistamine at doses close to those that produce H3 effects. Therefore, Sch 50971 is a novel, potent and selective agonist of histamine H3 receptors with an improved in vitro and in vivo receptor profile selectivity compared with (R)-alpha-methylhistamine.

Authors+Show Affiliations

Allergy, Schering-Plough Research Institute, Kenilworth, New Jersey, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9793613

Citation

Hey, J A., et al. "Studies On the Pharmacology of the Novel Histamine H3 Receptor Agonist Sch 50971." Arzneimittel-Forschung, vol. 48, no. 9, 1998, pp. 881-8.
Hey JA, Aslanian R, Bolser DC, et al. Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971. Arzneimittelforschung. 1998;48(9):881-8.
Hey, J. A., Aslanian, R., Bolser, D. C., Chapman, R. W., Egan, R. W., Rizzo, C. A., Shih, N. Y., Fernandez, X., McLeod, R. L., West, R., & Kreutner, W. (1998). Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971. Arzneimittel-Forschung, 48(9), 881-8.
Hey JA, et al. Studies On the Pharmacology of the Novel Histamine H3 Receptor Agonist Sch 50971. Arzneimittelforschung. 1998;48(9):881-8. PubMed PMID: 9793613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971. AU - Hey,J A, AU - Aslanian,R, AU - Bolser,D C, AU - Chapman,R W, AU - Egan,R W, AU - Rizzo,C A, AU - Shih,N Y, AU - Fernandez,X, AU - McLeod,R L, AU - West,R, AU - Kreutner,W, PY - 1998/10/30/pubmed PY - 1998/10/30/medline PY - 1998/10/30/entrez SP - 881 EP - 8 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 48 IS - 9 N2 - Experiments were performed to characterize the pharmacology of Sch 50971 ((+)-trans-4-(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H3 receptor agonist. The activity of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CAS 75614-87-8), a potent and moderately selective agonist of histamine H3 receptors, in a series of in vitro and in vivo assays. Sch 50971 is a high affinity, selective H3 receptor agonist in vitro and in vivo. Sch 50971 inhibits [3H]-N-alpha-methylhistamine (CAS 673-50-7) binding to the histamine H3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric field stimulated guinea pig ileum contractions (pD2 = 7.47) and decreases [3H]-norepinephrine (CAS 51-41-2) release (pD2 = 7.48) from guinea pig pulmonary artery by activation of presynaptic inhibitory H3 receptors. The in vitro effects of Sch 50971 are antagonized by low concentrations of a selective H3 antagonist, thioperamide (CAS 106243-16-7). Sch 50971 has low affinity (IC50's > 10 mumol/l) for histamine H1, dopamine D1 and D2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H3 agonist activity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/kg 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 assays, Sch 50971 exhibits an efficacy and potency comparable to H3-agonist (R)-alpha-methylhistamine. However, under in vivo conditions, Sch 50971 does not exhibit histamine H1-mediated responses that are seen with (R)-alpha-methylhistamine at doses close to those that produce H3 effects. Therefore, Sch 50971 is a novel, potent and selective agonist of histamine H3 receptors with an improved in vitro and in vivo receptor profile selectivity compared with (R)-alpha-methylhistamine. SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/9793613/Studies_on_the_pharmacology_of_the_novel_histamine_H3_receptor_agonist_Sch_50971_ L2 - https://www.lens.org/lens/search/patent/list?q=citation_id:9793613 DB - PRIME DP - Unbound Medicine ER -