Spirocyclic NK(1) antagonists I: [4.5] and [5.5]-spiroketals

A series of novel spiroketal-based NK(1) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.     

Spirocyclic NK(1) antagonists II: [4.5]-spiroethers

A series of novel spiroether-based neurokinin-1 (NK(1)) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.     

1-Phenyl-8-azabicyclo[3.2.1]octane ethers: a novel series of neurokinin (NK1) antagonists

1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK(1) receptor antagonists. Substitution at the 6-exo-position led to high affinity NK(1) antagonists with a prolonged duration of action in vivo. Incorporation of an alpha-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel.     

Eledoisin and Kassinin, but not Enterokassinin, stimulate ion transport in frog skin

In frog skin, tachykinins stimulate the ion transport, estimated by measuring the short-circuit current (SCC) value, by interacting with NK1-like receptors. In this paper we show that Kassinin (NK2 preferring in mammals) increases the SCC, while Enterokassinin has no effect. Therefore, either 2 Pro residues or 1 Pro and 1 basic amino acid must be present in the part exceeding the C-terminal pentapeptide. Eledoisin (NK3 preferring in mammals) stimulation of SCC is reduced by CP99994 and SR48968 (NK1 and NK2 antagonists) and not affected by SB222200 (NK3 antagonist). None of the three antagonists affects Kassinin stimulation of SCC.     

Biphenyl derivatives as novel dual NK(1)/NK(2)-receptor antagonists

In a continuation of our efforts to simplify the structure of our neurokinin antagonists, a series of substituted biphenyl derivatives has been prepared. Several compounds exhibit potent affinities for both the NK(1) receptor (<10nM) and for the NK(2) receptor (<50 nM). Details on the design, synthesis, biological activities, SAR and conformational analysis of this new class of dual NK(1)/NK(2) receptor antagonists are presented.     

Effect of subchronic administration of tachykinin antagonists on response of guinea-pigs to mild and severe stress

The effects of subchronic subcutaneous treatment with tachykinin receptor antagonists over nine days on the repeated mild stress response induced by daily subcutaneous injections and on the severe acute stress induced by morphine withdrawal were investigated in guinea-pigs. The NK(1) receptor antagonist, L733,060, 0.25mg/kg, significantly increased locomotor activity of guinea-pigs compared with animals subjected to repeated injection of the inactive enantiomer, but inhibited Fos-like immunoreactivity (Fos-LI) in the hypothalamus. In animals subjected to the acute severe stress of naltrexone-induced morphine withdrawal, treatment with the NK(1) antagonist, L733,060, produced reductions in Fos-LI in the spinal dorsal horn, whereas those treated with the NK(3) antagonist, SSR146,977, 0.3mg/kg, had reduced Fos-LI in the dorsal horn, adrenal medulla, nucleus accumbens, ventral tegmental area and periaqueductal grey. Those animals treated with both NK(1) and NK(3) antagonists also had reduced Fos-LI in the amygdala and paraventricular nucleus of the thalamus. It was concluded that the NK(1) antagonist reduced the hypothalamic response to mild stress but the NK(3) antagonist was more effective in reducing the severe stress response to morphine withdrawal. Furthermore, combination of NK(1) and NK(3) antagonists was more effective than either antagonist in reducing the Fos-LI response to morphine withdrawal.     

Discovery of novel, orally active dual NK1/NK2 antagonists

Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.     

The new neurokinin 1-sensitive receptor mediates the facilitation by endogenous tachykinins of the NMDA-evoked release of acetylcholine after suppression of dopaminergic transmission in the matrix of the rat striatum

Using an in vitro microsuperfusion procedure, the NMDA-evoked release of [3H]ACh was studied after suppression of dopamine (DA) transmission (alpha-methyl-p-tyrosine) in striatal compartments of the rat. The effects of tachykinin neurokinin 1 (NK1) receptor antagonists and the ability of appropriate agonists to counteract the antagonist responses were investigated to determine whether tachykinin NK1 classic, septide-sensitive and/or new NK1-sensitive receptors mediate these regulations. The NK1 antagonists, SR140333, SSR240600, GR205171 but not GR82334 and RP67580 (0.1 and 1 microM) markedly reduced the NMDA (1 mm + D-serine 10 microM)-evoked release of [3H]ACh only in the matrix. These responses unchanged by coapplication with NMDA of NK2 or NK3 agonists, [Lys5,MeLeu9,Nle10]NKA(4-10) or senktide, respectively, were completely counteracted by the selective NK1 agonist, [Pro9]substance P but also by neurokinin A and neuropeptide K (1 nM each). According to the rank order of potency of agonists for counteracting the antagonist responses ([Pro9]substance P, 0.013 nM > neurokinin A, 0.15 nM > substance P(6-11) 7.7 nM = septide 8.7 nM), the new NK1-sensitive receptors mediate the facilitation by endogenous tachykinins of the NMDA-evoked release of ACh in the matrix, after suppression of DA transmission. Solely the NK1 antagonists having a high affinity for these receptors could be used as indirect anti-cholinergic agents.     

A Structural Rationale for the Design of Water Soluble Peptide-Derived Neurokinin-1 Antagonists

Abstract

Molecular models of a pharmacophore for NK1 neurokinin antagonists and of ligand-receptor complexes for the human NK1 G protein-coupled receptor are presented. The models develop a structural rationale for the discovery of the recently described highly potent peptidomimetic NK1 antagonists S18523 and S19752 which were designed to be water soluble. Water solubility was conferred on these compounds by introduction of an anionic butyl-tetrazole substituent on the scaffold of dipeptide-derived NK1 antagonist analogues. The models provide convincing evidence that the anionic butyl-tetrazole moieties of S18523 and S19752 protrude outside the membrane-spanning domain of the receptor and do not interfere significantly with the core of the antagonist binding site. It is emphazised that this result could only be obtained through the combination of the two modelling approaches. The result suggest a general way to modify the transport properties of the peptidomimetic antagonists without altering the receptor-binding interaction, and it outlines the potential of including the combination of pharmacophore models and crude models of receptor-ligand complexes early in the drug design process.     

Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs

Neurokinin-1 (NK1) receptor antagonists have been reported to possess antidepressant and anxiolytic properties in controlled trials. Since antidepressant and anxiolytic drugs act mainly by enhancing serotonin (5-HT) and norepinephrine (NE) neurotransmission in forebrain areas, the main focus of the present review is to critically examine the electrophysiological effects of NK1 receptor antagonists on serotoninergic and noradrenergic neurons, and then hippocampal neurons. It is concluded that NK1 antagonists increase the firing and burst activity of 5-HT neurons, increase burst activity of NE neurons, and modulate postsynaptic transmission at the hippocampus level. Further research is needed in order to develop more selective ligands for the human NK1 receptor and to gain better knowledge of required brain penetration and optimal pharmacodynamic conditions for their use in patients.     

Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 antagonists

A series of 8-azabicyclo[3.2.1]octane amine hNK1 antagonists has been investigated and structure-activity relationships of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for hNK1 with selectivity over the hERG channel.     

Identification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia

During the lead optimization of NK(1)/NK(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK(1) and NK(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK(1)/NK(3) activity, were reported in this paper.     

Rational design of novel pyrrolidine derivatives as orally active neurokinin-3 receptor antagonists

The rational design of a novel series of pyrrolidine derivatives as neurokinin-3 receptor antagonists is reported starting from a selective neurokinin-1 receptor antagonist. Typical representatives in this series showed in vivo efficacy after oral administration in a NK3 mediated functional assay. This series of NK3 antagonists shows promise to deliver a novel antipsychotic.     

Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]-2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist

A novel series of dual NK(1)/NK(2) receptor antagonists, based on the 2-oxo-(1,4'-bipiperidine) template, has been prepared. Compound 10R is a potent dual NK(1)/NK(2) antagonist and demonstrates excellent in vivo activity and good oral plasma levels in the dog.     

Different subtypes of tachykinin NK(1) receptor binding sites are present in the rat brain

(2-[(125)I]iodohistidyl(1))Neurokinin A ([(125)I]NKA), which labels "septide-sensitive" but not classic NK(1) binding sites in peripheral tissues, was used to determine whether septide-sensitive binding sites are also present in the rat brain. Binding studies were performed in the presence of SR 48968 (NK(2) antagonist) and senktide (NK(3) agonist) because [(125)I]NKA also labels peripheral NK(2) binding sites and, as shown in this study, central NK(3) binding sites. [(125)I]NKA was found to label not only septide-sensitive binding sites but also a new subtype of NK(1) binding site distinct from classic NK(1) binding sites. Both subtypes of [(125)I]NKA binding sites were sensitive to tachykinin NK(1) antagonists and agonists but also to the endogenous tachykinins NKA, neuropeptide K (NPK), and neuropeptide gamma (NPgamma). However, compounds of the septide family such as substance P(6-11) [SP(6-11)] and propionyl-[Met(O(2))(11)]SP(7-11) and some NK(1) antagonists, GR 82334, RP 67580, and CP 96345, had a much lower affinity for the new NK(1)-sensitive sites than for the septide-sensitive sites. The hypothalamus and colliculi possess only this new subtype of NK(1) site, whereas both types of [(125)I]NKA binding sites were found in the amygdala and some other brain structures. These results not only explain the central effects of septide or SP(6-11), but also those of NKA, NPK, and NPgamma, which can be selectively blocked by NK(1) receptor antagonists.     

Effects of neurokinin receptor antagonists in virus-infected airways

We investigated the effects of a neurokinin-1 (NK(1)) receptor antagonist (SR-140333) and a NK(2) receptor antagonist (SR-48968) on airway responsiveness and on the function of neuronal M(2) muscarinic receptors, which normally inhibit vagal acetylcholine release, in guinea pigs infected with parainfluenza virus. Antagonists were given 1 h before infection and daily thereafter. Four days later, bronchoconstriction induced by either intravenous histamine (which is partly vagally mediated) or electrical stimulation of the vagus nerves was increased by viral infection compared with control. In addition, the ability of the muscarinic agonist pilocarpine to inhibit vagally induced bronchoconstriction was lost in virus-infected animals, demonstrating loss of neuronal M(2) receptor function. Macrophage influx into the lungs was inhibited by pretreatment with both antagonists. However, only the NK(1) receptor antagonist prevented M(2) receptor dysfunction and inhibited hyperresponsiveness (measured as an increase in either vagally induced or histamine-induced bronchoconstriction). Thus virus-induced M(2) receptor dysfunction and hyperresponsiveness are prevented by a NK(1) receptor antagonist, but not by a NK(2) receptor antagonist, whereas both antagonists had similar anti-inflammatory effects.     

Naphtho[2,1-b][1,5] and [1,2-f][1,4]oxazocines as selective NK1 antagonists

Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that model.     

Metalloelastase in lungs and alveolar macrophages is modulated by extracellular substance P in mice

Metalloelastase (MMP-12), mainly produced by macrophages, has been shown to play a key role in the pathogenesis of emphysema in animal models. Chronic cigarette smoke increases pulmonary MMP-12, which is closely correlated with an elevation of pulmonary substance P (SP). Because alveolar macrophages (AMs) contain the neurokinin-1 receptor (NK1R), we tested whether SP was able to trigger the upregulation of MMP-12 synthesis in AMs by acting on the NK1R. AMs isolated from bronchoalveolar lavage cells in C3H/HeN mice were cultured with control medium or SP that was coupled without or with NK1R antagonists (CP-99,994 or aprepitant) for 24 h. We found that SP significantly increased the mRNA of MMP-12 and NK1R by 11-fold and 82%, respectively, in AMs (P<0.05), and these responses were abolished by NK1R antagonists with little change in the cells' viability. Because pulmonary SP is primarily released by bronchopulmonary C-fibers (PCFs), we further asked whether destruction of PCFs would reduce SP and MMP-12. Two groups of mice were pretreated with vehicle and neonatal capsaicin (NCAP) to degenerate PCFs, respectively. Our results show that NCAP treatment significantly decreased mRNA and protein levels of SP associated with a reduction NK1R and MMP-12 in the lungs and AMs. These findings suggest that SP has a modulatory effect on pulmonary MMP-12 by acting on NK1R to trigger MMP-12 syntheses in the AMs.     

Synthesis and structure-activity relationships of oxime neurokinin antagonists: discovery of potent arylamides.

The structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK(1)/NK(2) antagonists.     

Design, structure-activity relationship, and highly efficient asymmetric synthesis of 3-phenyl-4-benzylaminopiperidine derivatives as novel neurokinin-1 receptor antagonists

We synthesized a series of novel 3-phenyl-4-benzylaminopiperidine derivatives that were identified as potent tachykinin NK(1) receptor antagonists by structural modification of the 3-benzhydrylpiperidone derivative through high-throughput screening. N-{2-[(3R,4S)-4-({2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}amino)-3-phenyl-1-piperidinyl]-2-oxoethyl}acetamide ((+)-39) was found to be one of the most potent tachykinin NK(1) receptor antagonists with high metabolic stability. Highly efficient asymmetric synthesis of (+)-39 was achieved via dynamic kinetic resolution.