Arthur A. Hancock

H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats

The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.

Perspectives on cognitive domains, H3 receptor ligands and neurological disease.

Histamine H3 receptor agonists and antagonists have been evaluated in numerous in vitro and in vivo animal models to better understand how H3 receptors modulate neurotransmitter function in the central nervous system. Likewise, behavioural models have explored the hypothesis that changes in neurotransmitter release could enhance cognitive function in human diseases. This review examines the reported effects of H3 receptor ligands and how they influence cognitive behaviour. These data are interpreted on the basis of different cognitive domains that are relevant to neuropsychiatric diseases. Because of the diversity of H3 receptors, their function and their influence on neurotransmitter systems, considerable promise exists for H3 ligands to treat diseases in which aspects of learning and memory are impaired. However, because of the complexities of the histaminergic system and H3 receptors and the lack of clinical data so far, proof of principle for use in human disease remains to be established.

Assessment of pharmacology and potential anti-obesity properties of H3 receptor antagonists/inverse agonists.

Histamine is a key neurotransmitter that alters central nervous system functions in both behavioural and homeostatic contexts through its actions on the histamine (H) subreceptors H1, H2 and H3 G-protein-coupled receptors. H3receptors have a diverse central nervous system distribution where they function as both homo- and hetero-receptors to modulate the synthesis and/or release of several neurotransmitters. H3 receptors are constitutively active, which implies that antagonists of H3 receptors may also function as inverse agonists to alter the basal state of the receptor and uncouple constitutive receptor–G-protein interactions. Reference H3 antagonists such as thioperamide and ciproxifan, administered either centrally or systemically, have been shown to cause changes in food consumption and/or body weight in proof-of-concept studies. More recently, several non-imidazole-based H3 antagonists/inverse agonists have also been described with efficacy in at least one animal model of human obesity. Considerable preclinical effort remains necessary before such compounds achieve therapeutic success or failure. Moreover, ongoing research in a number of laboratories has shed new insights into the effects of H3 ligands in the control of feeding, appetite and body weight, which offer different results and conclusions. The goal of this review is to appraise these findings and forecast whether any H3 antagonists/inverse agonists will provide clinical utility to treat human obesity.

Effects of histamine H3 receptor antagonists in two models of spatial learning

Despite the well-described attention and short-term memory enhancing effects of H3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic systems, there is a paucity of evidence for a role for H3 receptor blockade in spatial learning. To address this, we investigated two H3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H3 receptors in spatial learning that appears to be task-dependent.

Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H4 Receptor Ligands

A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.

An 80-Amino Acid Deletion in the Third Intracellular Loop of a Naturally Occurring Human Histamine H3 Isoform Confers Pharmacological Differences and Constitutive Activity

In this article, we pharmacologically characterized two naturally occurring human histamine H3 receptor (hH3R) isoforms, hH3R(445) and hH3R(365). These abundantly expressed splice variants differ by a deletion of 80 amino acids in the intracellular loop 3. In this report, we show that the hH3R(365) is differentially expressed compared with the hH3R(445) and has a higher affinity and potency for H3R agonists and conversely a lower potency and affinity for H3R inverse agonists. Furthermore, we show a higher constitutive signaling of the hH3R(365) compared with the hH3R(445) in both guanosine-5′-O-(3-[35S]thio) triphosphate binding and cAMP assays, likely explaining the observed differences in hH3R pharmacology of the two isoforms. Because H3R ligands are beneficial in animal models of obesity, epilepsy, and cognitive diseases such as Alzheimers disease and attention deficit hyperactivity disorder and currently entered clinical trails, these differences in H3R pharmacology of these two isoforms are of great importance for a detailed understanding of the action of H3R ligands.

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3 Receptor Antagonist

Blockade of the histamine H3 receptor (H3R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H3R antagonist 2-[4′-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H3Rs (Ki = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001–0.03 mg/kg), social recognition memory in adult rats (0.03–0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1–1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H3R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H3R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.

Detection of multiple H3 receptor affinity states utilizing [3H]A-349821, a novel, selective, non-imidazole histamine H3 receptor inverse agonist radioligand.

1 A‐349821 is a selective histamine H3 receptor antagonist/inverse agonist. Herein, binding of the novel non‐imidazole H3 receptor radioligand [3H]A‐349821 to membranes expressing native or recombinant H3 receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N‐α‐methylhistamine ([3H]NαMH). 2 [3H]A‐349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3 receptors with 10‐fold higher affinity compared to rat H3 receptors. [3H]A‐349821 detected larger populations of receptors compared to [3H]NαMH. 3 Displacement of [3H]A‐349821 binding by H3 receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3 receptor agonists was biphasic, suggesting recognition of both high‐ and low‐affinity H3 receptor sites. 4 pKi values of high‐affinity binding sites for H3 receptor competitors utilizing [3H]A‐349821 were highly correlated with pKi values obtained with [3H]NαMH, consistent with labelling of H3 receptors by [3H]A‐349821. 5 Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A‐349821, while displacement of [3H]A‐349821 binding by the H3 receptor agonist histamine was sensitive to GDP. 6 In conclusion, [3H]A‐349821 labels interconvertible high‐ and low‐affinity states of the H3 receptor, and displays improved selectivity over imidazole‐containing H3 receptor antagonist radioligands. [3H]A‐349821 competition studies showed significant differences in the proportions and potencies of high‐ and low‐affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors.

Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-activity relationships.

A new histamine H3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based on a previously identified conessine-based H3R antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H3 K(i) of 0.54 nM, rat H3 K(i) of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).

Cognitive enhancing effects of drugs that target histamine receptors

While histamine effects have been studied for decades in many classical experiments of basic pharmacology, and histamine is often used as a tool to elucidate fundamental pharmacological principles of drug-receptor interactions, it is only within recent years that its importance as a neurotransmitter has been recognized. This is despite findings of the substance within the CNS in the early 1900s, with a differential distribution and enzymes necessary for synthesis (for review, see [1]). As will be described below, new findings suggest important therapeutic roles for histamine and therapeutic potential for drugs that interdict the histaminergic pathways in various neurological diseases, particularly those having a cognitive deficit that these drugs may be anticipated to ameliorate (see Fig. 1 for chemical structures of key compounds discussed).