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This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.

Bisaryl cyclic ureas have been identified as high affinity 5-HT2C receptor antagonists with selectivity over 5-HT2A and 5-HT2B. Compounds such as 8 and 22 have shown oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function in rodents.

The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.

1. Although an important regulatory role for serotonin (5-HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5-HT receptor subtypes on seizure modulation. 2. The aim of the present study was to investigate the role of 5-HT(1A, 1B and 1D) receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. 3. The mixed 5-HT receptor agonists SKF 99101 (5-20 mg kg(-1) i.p.) and RU 24969 (1-5 mg kg(-1) i.p.), 0.5 h pretest, both produced marked dose-related increases in seizure threshold. These agents share high affinity for 5-HT(1A, 1B and 1D) receptors. 4. Antiseizure effects induced by submaximal doses of these agonists were maintained following p-chlorophenylalanine (150 mg kg(-1) i.p. x 3 days)-induced 5-HT depletion. 5. The anticonvulsant action of both SKF 99101 (15 mg kg(-1) i.p.) and RU 24969 (2.5 mg kg(-1) i.p.) was dose-dependently abolished by the selective 5-HT1B receptor antagonist SB-224289 (0.1-3 mg kg(-1) p.o., 3 h pretest) but was unaffected by the selective 5-HT1A receptor antagonist WAY 100635 (0.01-0.3 mg kg(-1) s.c., 1 h pretest). This indicates that 5-HT1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. 6. In addition, the ability of the 5-HT(1B/1D) receptor antagonist GR 127935 (0.3-3 mg kg(-1) s.c., 60 min pretest) to dose-dependently inhibit SKF 99101-induced elevation of seizure threshold also suggests possible downstream involvement of 5-HT1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT1D receptor antagonist. 7. Overall, these data demonstrate that stimulation of postsynaptic 5-HT1B receptors inhibits electroshock-induced seizure spread in rats.

The effects of the K+ channel activators, levcromakalim, pinacidil and diazoxide, at comparable antihypertensive doses, on acute glucose tolerance and glibenclamide-induced hypoglycaemia were examined in conscious spontaneously hypertensive rats (SHR). Levcromakalim (0.15 mg.kg-1 p.o.) and pinacidil (1.0 mg.kg-1 p.o.) caused a slight, but short-lived, impairment of glucose tolerance following oral or s.c. administration of glucose (2.0 g.kg-1). This effect, although small, was abolished by the beta-adrenoceptor blocker, propranolol (2.0 mg.kg-1 p.o.). Diazoxide (30.0 mg.kg-1 p.o.) caused a marked and sustained impairment of oral glucose tolerance and s.c. glucose tolerance, the profile of which was quantitatively and qualitatively different from levcromakalim or pinacidil and was not significantly affected by propranolol. Glibenclamide (1.0-10. mg.kg-1 p.o.) elicited a dose-related hypoglycaemic response. Levcromakalim or pinacidil had little or no significant effect on the hypoglycaemic response elicited by glibenclamide (3.0 mg.kg-1). Conversely, diazoxide both abolished and reversed glibenclamide-induced hypoglycaemia. We conclude that levcromakalim and pinacidil have only marginal and transient effects on glycaemic control in conscious SHR and that these disturbances are probably mediated indirectly via reflex activation of the sympathetic nervous system in response to blood pressure lowering. In addition, at active antihypertensive doses neither levcromakalim nor pinacidil significantly interfered with the ability of glibenclamide to reduce blood glucose concentration. Diazoxide's impairment of oral glucose tolerance, s.c. glucose tolerance and glibenclamide response confirms this drug's well known ability to activate pancreatic KATP channels.

The effects of the potassium channel activators (KCA) levcromakalim and RP52891 on NANCe nerve-mediated changes in pulmonary dynamics were investigated in the anaesthetized guinea-pig, using a newly-developed respiratory dynamics computer. Levcromakalim (0.025-0.2 mg/kg i.v.) and RP52891 (0.05-0.5 mg/kg i.v.) caused dose-dependent inhibition of NANCe nerve-mediated increases in airways resistance (RAW) and decreases in dynamic compliance (Cdyn). These effects of the KCAs persisted for at least 1 h. Unlike NANCe nerve-mediated responses, equivalent challenges with exogenously-administered substance P (SP; 10-25 micrograms/kg i.v.) and neurokinin A (NKA; 0.5-2.0 micrograms/kg i.v.) tended to produce progressively increasing responses but this effect was not statistically significant. Levcromakalim (0.2 mg/kg i.v.) and RP52891 (0.5 mg/kg i.v.) did not significantly decrease responses to exogenously-administered SP, although NKA-induced bronchoconstriction was attenuated. Glibenclamide (25 mg/kg i.v.) partially reversed the NANCe-inhibitory effects of levcromakalim (0.1 mg/kg i.v.) and RP52891 (0.25 mg/kg i.v.) and fully reversed their hypotensive effects. We have shown that levcromakalim and RP52891 inhibit bronchoconstrictor responses to NANCe nerve stimulation. This involves the opening of a glibenclamide-sensitive K(+)-channel and may represent effects at a pre-junctional site on NANCe neurones to reduce transmitter release.