Stereoselectivity of the histamine H3-presynaptic autoreceptor.
The effects of the enantiomers of two chiral analogues of histamine (alpha, N alpha-dimethylhistamine and N alpha-methyl-alpha-chloromethylhistamine) were studied at H3-autoreceptors modulating histamine release in rat brain slices. These compounds act as H3-receptor agonists, displaying a low potency relative to histamine (below 4%) but a pronounced stereoselectivity (ratio of 31 for the isomers of alpha, N alpha-dimethylhistamine and 183 for their halogenated analogues) was observed. The (+)isomers (corresponding to S-configurated L-histidine) were highly preferred at H3-receptors, whereas the (-)isomers were more potent at H2-receptors, no difference being observed at H1-receptors. In addition, no such stereoselectivity was observed for the two isomers of a chiral impromidine derivative: both Sopromidine and its S enantiomer acted as antagonists of histamine at H3-autoreceptors with similar potencies (Ki = 5.6 X 10(-8) M and 4.5 X 10(-8) M), whereas Sopromidine acted as an H2-receptor agonist and the S-enantiomer as an H2-receptor antagonist. Our results indicate that H3-autoreceptors are chemically stereoselective, with structural requirements different from those of H1- and H2-receptors.
J M
JM
Arrang
J C
JC
Schwartz
W
W
Schunack
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D017446:Impromidine; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013237:Stereoisomerism
D006633:Histamine Antagonists; D007093:Imidazoles; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D017981:Receptors, Neurotransmitter; D017446:Impromidine