Abstract
Novel, potent, and selective non-imidazole histamine H(3) receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 +/- 0.12, pK(B) 5.93 +/- 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 +/- 0.21, pK(B) 8.39 +/- 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 +/- 0.12, pK(B) 8.38 +/- 0.10), 31, exhibit high affinity for the histamine H(3) receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H(1) and H(2), receptor subtypes and a 100-fold selectivity in the sigma(1) binding assay. Compounds 30and 31 are the most potent, selective non-imidazole histamine H(3) receptor antagonists reported in the literature to date.
MeSH terms
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Animals
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Binding, Competitive
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Cerebral Cortex / metabolism
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Dimaprit / analogs & derivatives*
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Dimaprit / chemical synthesis*
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Dimaprit / chemistry
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Dimaprit / pharmacology
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Drug Design
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Guanidines / chemical synthesis*
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Guanidines / chemistry
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Guanidines / metabolism
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Guanidines / pharmacology
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Guinea Pigs
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Histamine Antagonists / chemical synthesis*
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Histamine Antagonists / chemistry
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Histamine Antagonists / metabolism
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Histamine Antagonists / pharmacology
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Ileum / drug effects
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Ileum / physiology
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In Vitro Techniques
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Ligands
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Muscle Contraction / drug effects
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / metabolism
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Pyrrolidines / pharmacology
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Radioligand Assay
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Receptors, Histamine H1 / metabolism
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Receptors, Histamine H2 / metabolism
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Receptors, Histamine H3 / drug effects*
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Receptors, Histamine H3 / metabolism
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Receptors, sigma / metabolism
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Structure-Activity Relationship
Substances
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Guanidines
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Histamine Antagonists
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Ligands
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N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine
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N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine
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Pyrrolidines
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Receptors, Histamine H1
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Receptors, Histamine H2
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Receptors, Histamine H3
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Receptors, sigma
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sigma1-binding protein, rat
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Dimaprit