The selective H(3) receptor agonist (R)-alpha-methylhistamine (R)-alpha-MeHA stimulates drinking in the adult rat. In the present study, we investigated the role of the H(3) receptor in mediating ...this behavior in a new dipsogenia model using the CD-1 mouse. In addition, the putative inverse agonists ciproxifan, thioperamide and clobenpropit; the reported antagonist (1R,2R)-4-2-(5,5-dimethylhex-1-ynyl)cyclopropylimidazole (GT-2331); and the putative neutral antagonist/weak partial agonist proxyfan were evaluated for possible differences in pharmacological activity in this new model. Water intake increased over baseline in a dose-related manner following intraperitoneal administration of 80, 160 or 240 micromol/kg (R)-alpha-MeHA, but this effect was dependent on age (P30<P60<P80=P120). 3H-N-alpha-methylhistamine binding studies showed no change in H(3) receptor density for the whole mouse brain at these ages. All subsequent studies employed P80 mice dosed with 240 micromol/kg (R)-alpha-MeHA. Ciproxifan (0.001-30 micromol/kg), thioperamide (0.01-10 micromol/kg), clobenpropit (0.1-30 micromol/kg) and GT-2331 (0.03-10 micromol/kg) attenuated drinking dose-dependently, blocking the response completely at the highest doses in each case. In contrast, proxyfan (0.001-10 micromol/kg) only partially attenuated drinking elicited by (R)-alpha-MeHA: coadministration of proxyfan and ciproxifan resulted in an attenuation of ciproxifan's effects. This new dipsogenia model provides the first in vivo behavioral evidence for possible pharmacological differences between three putative H(3) receptor inverse agonists, GT-2331 and proxyfan.
The histamine H
4 receptor (H
4R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H
4R 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
1R antagonist diphenhydramine, H
2R antagonists ranitidine, or H
3R 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.
Blockade of presynaptic histamine H
3 receptors with potent and selective ligands improves cognitive function in rodents and there is significant interest in developing such drugs for long-term ...symptomatic treatment of CNS disorders such as attention deficit hyperactivity disorder (ADHD). Unfortunately, little is known about the effects of repeated exposure to H
3 receptor antagonists/inverse agonists. We therefore investigated the effects of acute and repeated daily administration of two potent, brain penetrating H
3 receptor antagonists/inverse agonists, ciproxifan and A-304121, on rat body weight, food and water intake, core temperature and locomotor activity, as well as H
3 receptor density and gene expression levels. Methylphenidate, used clinically for the treatment of ADHD, was included as an additional comparator. Ciproxifan, an imidazole-based compound, decreased food intake over the first 10 days and locomotor activity acutely, but these effects were lost after further repeated administration. The ex vivo binding studies revealed increased H
3 receptor density in rats following repeated administration of ciproxifan for 10 or 15 days; however, H
3 receptor gene expression was not changed. In contrast, rats treated with the non-imidazole, A-304121, did not differ from controls on any measure during the observation period, while rats treated with methylphenidate exhibited hyperthermia and hyperactivity. The implications for potential long-term treatment with H
3 receptor antagonists in CNS disorders such as ADHD are discussed.
The histamine H
3 receptor is predominantly expressed in the central nervous system and plays a role in diverse physiological mechanisms. In the present study, the effects of GSK189254, a potent and ...selective H
3 antagonist, were characterized in preclinical pain models in rats. Systemic GSK189254 produced dose-dependent efficacy (ED
50
=
0.77
mg/kg i.p.) in a rat model of monoiodoacetate (MIA) induced osteoarthritic (OA) pain as evaluated by hindlimb grip force. The role of H
3 receptors in regulating pain perception was further demonstrated using other structurally distinct H
3 antagonists. GSK189254 also displayed efficacy in a rat surrogate model indicative of central sensitization, namely phase 2 response of formalin-induced flinching, and attenuated tactile allodynia in the spinal nerve ligation model of neuropathic pain (ED
50
=
1.5
mg/kg i.p.). In addition, GSK189254 reversed persistent (CFA) (ED
50
=
2.1
mg/kg i.p,), whereas was ineffective in acute (carrageenan) inflammatory pain. When administered intrathecally (i.t.) to the lumbar spinal cord, GSK189254 produced robust effects in relieving the OA pain (ED
50
=
0.0027
mg/kg i.t.). The systemic GSK189254 effect was completely reversed by the α-adrenergic receptor antagonist phentolamine (i.p. and i.t.) but not by the opioid receptor antagonist naloxone (i.p.). Furthermore, the i.t. GSK189254 effect was abolished when co-administered with phentolamine (i.t.). These results suggest that the spinal cord is an important site of action for H
3 antagonism and the effect can be associated with activation of the noradrenergic system. Our data also provide support that selective H
3 antagonists may represent a class of agents for the treatment of pain disorders.
►H
3 receptor antagonism exhibits antinociceptive effects in the inflammatory and neuropathic pain models in rats. ►Antinociceptive action of H
3 antagonism has also been shown in a preclinical osteoarthritic pain model. ►The spinal cord is an important site of action for H
3 antagonism and the effect can be associated with activation of the noradrenergic systems. ►The selective H
3 receptor antagonists may be an attractive approach for the development of new drugs useful in the management of pain disorders associated with central mechanisms.
Abstract only
It is widely recognized that histamine is a mediator of itch and recent reports implicate the histamine H
4
receptor (H
4
R) in this response. We have synthesized two novel H
4
R ...antagonists, A‐943931 4‐ ((R) ‐3‐amino‐ pyrrolidin‐1‐yl) ‐6,7‐ dihydro ‐ 5H‐benzo 6,7 cyclohepta 1,2‐d pyrimidin‐2‐ylamine and A‐987306 4‐piperazin‐1‐yl‐5,6,7a,8,9,10,11,11a‐octahydro‐7‐oxa‐1,3‐diaza‐benzoc fluoren‐2ylamine as potent and selective H
4
R antagonists with high affinity at both human (K
i
s = 4.6 and 5.7 nM) and rat (K
i
s = 3.8 and 3.4 nM) receptors, respectively. A‐943931 and A‐987306 competitively and potently antagonize rat H
4
R agonist‐mediated responses in
35
SGTPγS binding assays (K
b
s = 28 and 6 nM) and intracellular calcium mobilization at rat and human receptors (K
b
s from 5‐10 nM). When tested
in vivo
in a mouse model of clobenpropit (10 nM, i.d.) induced scratching, A‐943931 inhibited the scratching response (IC
50
= 26 μmoles/kg, i.p.) with significant inhibition (69%) at the highest tested dose (30 μmoles/kg, i.p.). A‐987306 also inhibited the scratching response (IC
50
= 0.4 μmoles/kg, i.p.) with (85%) inhibition seen at 30 μmoles/kg, i.p. Our results show that A‐943931 and A‐987306 are potent and selective H
4
R antagonists with robust antipruritic activity and are useful tools for further exploration of the role of H
4
R receptors
in vivo. Research supported by Abbott Laboratories.
2-Aminoethylbenzofurans constitute a new class of H
3 antagonists that are more rotationally constrained than most previously reported H
3 antagonists. They retain high potency at human and rat ...receptors, with efficient CNS penetration observed in
35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.
Benzofurans such as
46 are a new class of non-imidazole histamine H
3 antagonists that reduce the rotatable bond count from the known pharmacophore.
46: rat cortex
K
i=3.22 nM, human
K
i=0.45 nM.
We have recently identified three splice isoforms of the histamine H sub(3) receptor in multiple brain regions of cynomolgus monkey (Macaca fascicularis). Two of the novel isoforms displayed a ...deletion in the third intracellular loop (H sub(3)(413) and H sub(3)(410)), the third isoform H sub(3)(335) displayed a deletion in the i3 intracellular loop and a complete deletion of the putative fifth transmembrane domain TM5. We have confirmed by RT-PCR the expression of full-length H sub(3)(445) mRNA as well as H sub(3)(413), H sub(3)(410), and H sub(3)(335) splice isoform mRNA in multiple monkey brain regions including the frontal, parietal and occipital cortex, parahippocampal gyrus, hippocampus, amygdala, caudate nucleus, putamen, thalamus, hypothalamus, and cerebellum. The full-length isoform H sub(3)(445) was predominant in all of the regions tested, followed by H sub(3)(335), with the H sub(3)(413) and H sub(3)(410) being of low abundance. When expressed in C6 cells, H sub(3)(445), H sub(3)(413), and H sub(3)(410) exhibit high affinity binding to the agonist ligand super(3)H-(N)- alpha -methylhistamine with respective pK sub(D) values of 9.7, 9.7, and 9.6. As expected, the H sub(3)(335) isoform did not display any saturable binding with super(3)H- (N)- alpha -methylhistamine. The histamine H sub(3) receptor agonists histamine, (R)- alpha -methylhistamine, imetit and proxyfan were able to activate calcium mobilization responses through H sub(3)(445), H sub(3)(413) and H sub(3)(410) receptors when they were co-expressed with the chimeric G alpha sub(qi5)-protein in HEK293 cells, while no response was elicited in cells expressing the H sub(3)(335) isoform. The existence of multiple H sub(3) receptor splice isoforms across species raises the possibility that isoform specific properties including ligand affinity, signal transduction coupling, and brain localization may differentially contribute to observed in vivo effects of histamine H sub(3) receptor antagonists.
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