Neurokinin NKi receptor

Several mediators have been implicated in the plasma leakage associated with airway inflammation. Most of these mediators have relatively transient effects on vascular permeabUity, because of the existence of mechanisms that limit the duration of their effects. For example, the action of substance P on vascular endothelial ceUs is Umited by the phosphorylation and internalization of neurokinin (Nki) receptors (Bowden et al., 1994a) and by the degradation of substance P by neutral endopeptidase and other enzymes (Umeno et al., 1989 Nadel, 1992 Katayama etal., 1993). 

Aroylpyridine-2-carboxylic acids 104 were used as the starting compounds for the preparation of 7-methyl-l,7-naphthyridin-8(7//)-one derivatives 105, which are new strong neurokinin NKi-receptor antagonists (1995JMC3106). 

Derivatives of annulated benzoindolo-l,5-naphthyridines attempting to improve memory were described (1985FRP2548667, 1987BCJ3797). These are benzo[Z>][l,5]nap-hthyridines, which are analogs of inhibitors of neurokinin NKi-receptors. Various 1,5-naphthyridine derivatives, in particular, 2-naphthyridinecarboxamide, possessing antiviral activity were also reported (1999PIAW09929318). 

Drug-drug interactions See Neurokinin NKi receptor antagonists below. 

The neurokinin, substance P (SP), may be involved as a sensory transmitter in afferent vagal nerves involved in the vomiting reflex. Both SP and its receptors (NKi receptors) have been detected in several areas of the brain associated with vomiting, including the AP, NTS and dorsal motor vagal nucleus. The neurokinin can activate neurons in the AP and NTS. SP is present also in sensory nerves in the gut as well as being co-localised with serotonin in some enterochromaffin cells. 

Neurokinin-1 Receptor. A homology model of the neurokinin-1 (NKi) receptor was built from the X-ray structure of rhodopsin, using the MOBILE (modeling binding sites including ligand information explicitly) approach. In this procedure, a preliminary model is generated, which is afterwards refined... 

Neurokinin receptors NK2 receptor agonists (e.g. GR64349) have an anxiogenic profile in animal models while the antagonists (GR100679) have an anti-anxiety effect. However, NKi receptor antagonists have also been reported to have antianxiety activity in the social interaction test (File 1997). 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

The actions of substance P and neurokinins A and are mediated by three G protein-coupled tachykinin receptors designated NK i, NK 2, and NK 3. Substance P is the preferred ligand for the NK receptor, the predominant tachykinin receptor in the human brain. However, neurokinins A and also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NKi receptors. All three receptor subtypes are coupled to inositol trisphosphate synthesis and calcium mobilization. 

MePhe lNKB is a neurokinin B derivative, a TACHYKININ RECEPTOR AGONIST reasonably selective at the NKy-receptor subtype. It is used as a pharmacological tool. 

To obtain neurokinin-1 (NKi) receptor antagonists. Cooper and co-workers [410] synthesized a series of variously substituted indoles by means of a Fischer indole synthesis on a solid phase. Thus, EUman resin [411], based on Kenner s safety-catch Hnker [318], was first reacted with 4-(4-chlorobenzoyl)butyric acid affording (598) and then treated with differently substituted phenyUiydrazines, affording the required indoles (599). These compounds were then cleaved from the resin using bromoacetonitrile, and subsequently coupled in solution with the desired amines under standard conditions (600) (Scheme 125). 

Assays utilizing coelenterazine-charged aequorin as a probe for intracellular calcium level have been used to investigate a wide variety of receptors endothehn ETa, angiogensin ATn, tyrosine-releasing hormone (TRH), and neurokinin NKi [170] 5-hydroxytryptamine 2A [171], and human EPl prostanoid receptor [172]. 

Long-chain terpenes, SCH 60065 (11) and nine other related analogs, have been isolated from Acremonium sp. (Hedge et al., 1997). These compounds are neurokinin (NK) receptor inhibitors with IC50 values ranges of 2.5 -11 pM (NKi) and 6.8-16 pM (NK2). 

SCHEME 2.19. Merck synthesis of neurokinin-1 (NKi) receptor antagonist 120. 

Pseudoephedrine was used as a chiral auxiliary in Merck s synthesis of neurokinin-1 (NKj receptor antagonists 226. NKi receptor antagonists have been shown to prevent acute delayed chemotherapy-induced nausea and vomiting. The enolate of (f ,f )-pseudoephedrine amide 222 was formed by reaction with LiHMDS in the presence of TMEDA, and subsequent reaction with ot,p-unsaturated ester afforded the desired product 224 in 56% yield with the required diastereoisomer as the major product. Following reduction of the ester functionality, the chiral auxiliary was removed via acid induced cyclisation to afford lactone 225. This was transformed into NKi receptor antagonist 226 in eight steps (Scheme 14.77). 

There is interest in the neurokinins (substance P, neurokinin A and neurokinin B) and their receptors (NKi, NK2 and NK3) as possible targets for antidepressant and antipsychotic drags. 

CRF Corticotrophin-releasing factor NKi Neurokinin receptor, type 1... 

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