The classification of histamine receptors has to date been based on rigorous classical pharmacological analysis, and as yet, the classification of the three histamine receptors that have been defined by this process, (i.e., the H1-, H2-, and H 3-receptors) have not been added to because of more

https://pharmrev.aspetjournals.org/content/pharmrev/49/3/253.full.pdf

International Union of Pharmacology. XIII. Classification of Histamine Receptors

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.

Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase.

The hypothalamic orexin (hypocretin) neuropeptides are associated with the regulation of sleep and feeding, and disturbances in orexinergic neurotransmission lead to a narcoleptic phenotype. Histamine has also been shown to play a role in the regulation of sleep and feeding. Therefore, we studied the relationship between the orexin and histamine systems of the CNS using electrophysiology, immunocytochemistry, and the reverse transcriptase (RT)-PCR method. Both orexin-A and orexin-B depolarized the histaminergic tuberomammillary neurons and increased their firing rate via an action on postsynaptic receptors. The depolarization was associated with a small decrease in input resistance and was likely caused by activation of both the electrogenic Na + /Ca 2+ exchanger and a Ca 2+ current. In a single-cell RT-PCR study using primers for the two orexin receptors, we found that most tuberomammillary neurons express both receptors and that the expression of the orexin-2 receptor is stronger than that of the orexin-1 receptor. Immunocytochemical studies show that the histamine and orexin neurons are often located very close to each other. The contacts between these two types of neurons seem to be reciprocal, because the orexin neurons are heavily innervated by histaminergic axons. These results suggest a functional connection between the two populations of hypothalamic neurons and that they may cooperate in the regulation of rapid-eye-movement sleep and feeding.

https://www.jneurosci.org/content/jneuro/21/23/9273.full.pdf

Orexin/Hypocretin Excites the Histaminergic Neurons of the Tuberomammillary Nucleus

Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein–coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.

https://pharmrev.aspetjournals.org/content/pharmrev/67/3/601.full.pdf

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Molecular pharmacological aspects of histamine receptors.

In dibutyryl-cAMP-differentiated HL-60 cells, histamine H1 and formyl peptide receptors mediate increases in the cytosolic Ca2+ concentration ([Ca2+]i) via pertussis toxin-sensitive G proteins of the Gi family. We compared the effects of 2-(3-chlorophenyl)-histamine (CPH) [2-[2-(3-chlorophenyl)-1H-imidazol-4-yl] ethanamine], one of the most potent and selective H1 receptor agonists presently available, with those of histamine and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) in these cells. CPH increased [Ca2+]i through Ca2+ mobilization and Ca2+ influx. Unlike histamine-induced rises in [Ca2+]i, those induced by CPH were not desensitized in a homologous manner, and there was no cross-desensitization between CPH and histamine. Like fMLP, CPH activated phospholipases C and D, tyrosine phosphorylation, superoxide anion formation, and azurophilic granule release. The effects of CPH on [Ca2+]i, phospholipase D, and superoxide anion formation were inhibited by pertussis toxin. CPH and fMLP stimulated high affinity GTP hydrolysis by Gi proteins in HL-60 membranes. They also enhanced binding of guanosine-5'-O-(3-thio)triphosphate and GTP azidoanilide to, and cholera toxin-catalyzed ADP-ribosylation of, Gi protein alpha subunits. Histamine receptor antagonists did not inhibit the stimulatory effects of CPH, and CPH did not reduce fMLP binding in HL-60 membranes. Our data suggest that CPH activates Gi proteins in HL-60 cells through a receptor agonist-like mechanism that is, however, independent of known histamine receptor subtypes and formyl peptide receptors. CPH may be an agonist at an as yet unknown histamine receptor subtype or, by analogy with other cationic-amphiphilic substances, may activate G proteins directly. Future studies will have to take into consideration the fact that CPH, in addition to activating H1 receptors, may show other, most unexpected, stimulatory effects on G protein-mediated signal transduction processes.

The H1 receptor agonist 2-(3-chlorophenyl)histamine activates Gi proteins in HL-60 cells through a mechanism that is independent of known histamine receptor subtypes.

2-Substituierte Imidazol-4-alkohole (3) lassen sich aus Alkyl- oder Aryliminoestern (1) und α-Hydroxyketonen (2) in flussigem Ammoniak unter Druck mit guten Ausbeuten darstellen.



A New Synthesis of Imidazole Derivatives



The 2-substituted imidazole-4-alcohols (3) are obtained from alkyl- or aryl-iminoesters (1) and α-hydroxy-ketones (2) in liquid ammonia under pressure in good yields.

Eine neue Synthese von Imidazolderivaten. 1. Mitt.: Zur Darstellung 2-substituierter Imidazol-4-alkohole

Als potentiell histaminartig wirksame Substanzen wurden 4-substituierte Piperidyl- und Aminocyclohexyl-imidazole dargestellt. Von diesen erwiesen sich 4-(3-Piperidyl)-imidazol (4b) und 4-(2-Aminocyclohexyl)-imidazol (8a) als histaminomimetisch wirksam. Uber Struktur-Wirkungs-Beziehungen der Histaminanaloga mit cyclisierter Seitenkette des Histaminmolekuls wird be richtet.



Histamine-like Compounds with Cyclized Side Chain



As substances with possible histamine-like activity 4-substituted piperidyl- and aminocyclohexyl-imidazoles were prepared. Two of them, 4-(3-piperidyl)-imidazole (4b) and 4-(2-aminocyclohexyl)-imidazole (8a), have histamine-like activity. Structure-action relationships of histamine analogs with cyclized side chain of the histamine molecule are reported.

Histaminähnliche Verbindungen mit cyclisierter Seitenkette 1. Mitt. über Struktur‐Wirkungs‐Beziehungen bei Histaminanaloga

Imidazol-4-carbinole 3 mit funktionellen Gruppen am C-Atom 2 lassen sich aus Iminoestern 1 und Dihydroxyaceton (2) in flussigem Ammoniak unter Druck darstellen.



Imidazole-4-carbinols from Iminoesters and Dihydroxyacetone



Imidazole-4-carbinols 3 with functional groups at C-atom 2 are obtained from iminoesters 1 and dihydroxyacetone (2) in liquid ammonia under pressure.

Walter Schunack

Papers

The H1 receptor agonist 2-(3-chlorophenyl)histamine activates Gi proteins in HL-60 cells through a mechanism that is independent of known histamine receptor subtypes.

Eine neue Synthese von Imidazolderivaten. 1. Mitt.: Zur Darstellung 2-substituierter Imidazol-4-alkohole

Histaminähnliche Verbindungen mit cyclisierter Seitenkette 1. Mitt. über Struktur‐Wirkungs‐Beziehungen bei Histaminanaloga

Imidazol‐4‐carbinole aus Iminoestern und Dihydroxyaceton. 2. Mitt. über Imidazolsynthesen mit flüssigem Ammoniak

The selective histamine H1-receptor agonist 2-(3-trifluoromethylphenyl)histamine increases waking in the rat