The broad-spectrum anti-emetic activity of the novel non-peptide tachykinin NK1 receptor antagonist GR203040.

1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have examined the anti-emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.     

Pharmacological profile of GR117289 in vitro: a novel, potent and specific non-peptide angiotensin AT1 receptor antagonist.

1. This paper describes the effects of GR117289 (1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzo-furanyl]methyl ]-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid) at angiotensin receptors and binding sites in rabbit aorta, rat liver and bovine cerebellum preparations in vitro. 2. In rabbit isolated aortic strips, GR117289 (0.3, 1 and 3 nM) caused a concentration-related, insurmountable suppression of the concentration-response curve to angiotensin II (AII). When the contact time was increased, a greater degree of antagonism of AII was observed, suggesting that GR117289 is slow to reach equilibrium. A pKB of 9.8 +/- 0.1 was calculated for GR117289 after 3 h incubation. GR117289 (1 microM) did not affect contractile responses to phenylephrine or 5-hydroxytryptamine (5-HT) in the rabbit aorta. 3. GR117289 (1 nM) alone caused a marked suppression and a slight rightward displacement of the AII concentration-response curve. Co-incubation with the competitive, surmountable AT1 receptor antagonist, losartan (10 nM, 100 nM and 1 microM), resulted in a concentration-related upward and rightward displacement of the concentration-response curve to subsequently administered AII. In separate experiments in which preparations were pre-incubated with GR117289 (1 nM), subsequent addition of losartan (1 microM) for 2, 15 or 45 min caused a further, but similar, rightward displacement of the concentration-response curve to subsequently administered AII with a time-dependent increase in the maximum response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative,general pharmacology of SDZ NKT 343, a novel,selective NK1 receptor antagonist

1. The in vitro and in vivo pharmacology of SDZ NKT 343 (2-nitrophenyl-carbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide), a novel tachykinin NK₁ receptor antagonist was investigated.
2. SDZ NKT 343 inhibited [³H]-substance P binding to the human NK₁ receptor in transfected Cos-7 cell membranes (IC₅₀=0.62±0.11 nM). In comparison, in the same assay K_i values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13±0.04 nM, 0.96±0.20 nM, 0.15±0.06 nM and 1.77±0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK₁ receptors in whole forebrain membranes (IC₅₀=451±139 nM).
3. SDZ NKT 343 caused an increase in EC₅₀ as well as reduction in the number of binding sites (B_max) determined for [³H]-substance P, suggesting a non-competitive interaction at the human NK₁ receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca²⁺]_i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar⁹]SP sulphone-induced contraction of the guinea-pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible.
4. SDZ NKT 343 showed weak affinity to human NK₂ and NK₃ receptors in transfected Cos-7 cells (K_i of 0.52±0.04 μM and 3.4±1.2 μM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B₂ receptor the histamine H₁ receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca²⁺ and Na⁺currents in guinea-pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)-SDZ NKT 343 was about 1000 times less active at human NK₁ receptors expressed in Cos-7 cell membranes.
5. Contractions of the guinea-pig ileum by [Sar⁹]SP sulphone were inhibited by SDZ NKT 343 in a concentration-dependent manner, with an IC₅₀=1.60±0.94 nM, while the enantiomer (R,R)-SDZ NKT 343 was 100 times less active (IC₅₀=162±26 nM). In comparison, in the same assay IC₅₀ values for other NK₁ receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90±07 nM, 0.14±0.02 nM, 11.4±2.9 nM and 2.4±0.83 nM, respectively.
6. In anaesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar⁹]SP sulphone-evoked bronchoconstriction (70% reduction at 0.4 mg kg⁻¹, i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected.
7. In conclusion, SDZ NKT 343 is a highly selective NK₁ receptor antagonist with high potency at the human and guinea-pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK₁ receptor hyperfunction is involved.

     

The airways pharmacology of DNK333, a potent,selective, non‐peptide dual NK1/NK2 receptor antagonist

The airways' pharmacology of DNK333 ((1R,3R,2E)‐N‐[3,4‐dichlorobenzyl)]‐4‐[(hexahydro‐2‐oxo‐1H‐azepin‐3‐yl)amino]‐N‐methyl‐3,5bis(trifluoromethyl) benzamide), a potent and selective dual NK₁/NK₂ neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK₁ and NK₂ receptors. In guinea‐pig isolated trachea, DNK333 induced concentration‐dependent blockade of the contractile responses to NK₁‐ or NK₂‐receptor agonists. In anaesthetized guinea‐pigs, DNK333 shifted the bronchoconstrictor dose‐response curves induced by NK₁‐ and NK₂‐receptor agonists by 21.8‐ (3 mg/kg) and 6.8‐fold (10 mg/kg), respectively. At 10 mg/kg, a 12‐h duration of action was observed. Nasal perfusion of substance P and capsaicin to anaesthetized guinea‐pigs induced extravasation, which was inhibited dose‐dependently by DNK333 (ED₅₀ values 72 and 70 µg/kg, respectively). Exposure of conscious guinea‐pigs to 0.6 M citric acid resulted in cough and an increase in enhanced pause of respiratory function (Penh). Oral administration of DNK333 (0.3, 3, or 10 mg/kg, ?2 h) inhibited cough by 62, 63, and 82%, respectively and the increase in Penh by 85.5 and 77.2% (3 and 10 mg/kg, respectively). Bronchoconstrictor responses in anaesthetized guinea‐pigs to intravenous injections of methacholine and substance P were increased 60 min after LPS challenge (1 mg/kg, i.v.). DNK333 (1 and 10 mg/kg) dosed intraduodenally 30 min prior to LPS challenge inhibited airway hyperreactivity in a dose‐dependent manner. In conclusion, DNK333 is a potent, orally bioavailable, dual NK₁/NK₂ receptor antagonist with a long duration of action. It inhibits bronchoconstriction, extravasation, cough, and airway hyperreactivity induced by endogenous release of neuropeptides, which renders DNK333 suitable for exploring the role of tachykinins in respiratory disease. Drug Dev Res 63:161–173, 2004. © 2004 Wiley‐Liss, Inc.     

MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon

We have characterized the action of the novel, water-soluble, tachykinin NK₂ receptor antagonist MEN 11420 ([Asn(2-AcNH-β-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2β–5β)) on the circular muscle of the guinea-pig and human colon in vitro and on the guinea-pig colon in vivo. In organ bath experiments on guinea-pig colon MEN 11420 produced a concentration-dependent rightward shift of the concentration-response curve to the NK₂ receptor selective agonist, [βAla⁸]neurokinin A (NKA) (4–10) with a pK_B value of 8.1. Up to 1 μM MEN 11420 had no effect on the concentration-response curve to methacholine, to the NK₁ receptor selective agonist, [Sar⁹]substance P (SP) sulfone, to the NK₃ receptor selective agonist, senktide, or on the response to exogenous SP. The response to exogenous NKA was inhibited, although the shift of the concentration-response curve to NKA produced by MEN 11420 at 1 μM (dose ratio 5.3) was much smaller than that produced against [βAla⁸]NKA (4–10) (dose ratio 102), presumably because NKA also stimulates NK₁ receptors at relatively low concentrations. In sucrose gap, MEN 11420 concentration-dependently inhibited both depolarization (IC₅₀ 0.34 μM) and contraction (IC₅₀ = 0.32 μM) produced by [βAla⁸]NKA (4–10) (0.3 μM for 10 s) in the guinea-pig colon without affecting the corresponding responses produced by [Sar⁹]SP sulfone. When similar experiments were performed in the circular muscle of the human colon MEN 11420 concentration-dependently inhibited both depolarization and contraction induced by [βAla⁸]NKA(4– 10) with IC_50s of 99 and 75 nM, respectively. MEN 11420 (1 μM) had no effect on the nonadrenergic noncholinergic (NANC) depolarization and contraction produced by a short period of electrical field stimulation (EFS, 10 Hz for 1 s) in the guinea-pig colon and selectively inhibited the sustained component of depolarization produced during a prolonged period of EFS (3 Hz for 3 min), without affecting the concomitant depolarization. Nifedipine (1 μM) eliminated the NANC contraction to a short period of EFS and the phasic contraction in response to a prolonged period of EFS. MEN 11420 (1 μM) abolished the nifedipine-resistant NANC contraction produced by prolonged period of electrical field stimulation (EFS, 3 Hz for 3 min). All electrical and mechanical NANC responses to EFS which were resistant to MEN 11420, either in the absence or presence of nifedipine, were abolished by the subsequent application of the NK₁ receptor antagonist, SR 140333 (1 μM). Up to 3 μM, MEN 11420 had no significant effect on the cholinergic excitatory junction potential or the NANC inhibitory junction potential evoked by single pulse EFS, nor did it affect membrane conductance. In urethane-anaesthetized guinea-pigs MEN 11420 (10– 100 nmol/kg i.v.) produced a dose-dependent and long lasting (> 3 h) inhibition of the contractile response (15 ± 2 mmHg) of the proximal colon induced by [βAla⁸]NKA (4–10) (3 nmol/kg i.v.). MEN 11420 (300 nmol/kg i.v.) did not affect the contraction produced by [Sar⁹]SP sulfone. MEN 11420 (300 nmol/kg) produced a limited (Emax about 40% inhibition) and transient (recovery within 60 min) inhibition of the atropine- and hexamethonium-sensitive phasic contractions of the proximal colon induced by threshold distension of a colonic balloon. On the other hand, MEN 11420 (10–300 nmol/kg i.v.) produced a dose-dependent complete and prolonged (> 2 h from administration) inhibition of the atropine-resistant and hexamethonium-sensitive phasic contraction induced by suprathreshold distension of the colonic balloon. We conclude that MEN 11420 is a potent and selective tachykinin NK₂ receptor antagonist devoid of significant inhibitory activity toward excitatory transmission mediated via tachykinin NK₁ or muscarinic receptors. The present findings indicate that SP and NKA are likely involved in the preferential activation of NK₁ and NK₂ receptors during tachykininergic transmission, although NKA can act as an effective NK₁ receptor ligand. Received: 24 March 1997 / Accepted: 9 June 1997     

MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist

The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2相似文献   

The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation.

1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.     

The selective tachykinin neurokinin 1 (NK1) receptor antagonist, GR 205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms

Circadian rhythms in mammals are generated by master pacemaker cells located within the suprachiasmatic nucleus of the hypothalamus. In hamsters, the suprachiasmatic nucleus contains a small collection of cells immunoreactive for substance P, the endogenous ligand of tachykinin neurokinin 1 (NK1) receptors. In addition, two other nuclei which form part of the circadian system, the intergeniculate leaflet of the thalamus and the raphe nuclei, also contain fibers and/or cell bodies immunoreactive for substance P. In light of these observations, we evaluated the influence of the selective tachykinin NK1 receptor antagonist, GR 205,171, upon circadian activity rhythms in the hamster. Systemic injection of GR 205,171 dose-dependently (2.5-40.0 mg/kg, i.p.) inhibited light-induced phase advances in hamster circadian wheel running activity rhythms by approximately 50%. In contrast, GR 226,206, the less active enantiomer of GR 205,171, failed to affect light-induced phase advances. In addition, we examined the potential ability of GR 205,171 to induce non-photic phase shifts in hamster wheel running rhythms when injected at mid-day to late night circadian times. However, GR 205,171 (40 mg/kg) did not elicit non-photic phase shifts at these times indicating that tachykinin NK1 receptor antagonists are only effective when a light stimulus is applied to the pacemaker. Although GR 205,171 may, in theory, activate several sites within the circadian system, we suggest that GR 205,171 acts in the raphe nuclei to increase inhibitory serotonergic input to pacemaker cells in the suprachiasmatic nuclei, thereby suppressing photic modulation of the pacemaker. These findings have important implications for the use of tachykinin NK1 receptor antagonists in the treatment of depression and other central nervous system disorders.     

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

(S)1- {;2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl };-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK₁ receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK₁ receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK₁ receptors such as [Sar⁹,Met(O₂)¹¹]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 μM, it had no effect in bioassays for NK₂ ([βAla⁸]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK₃ ([MePhe⁷]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK₁ receptors was apparently non-competitive, with pD'₂ values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar⁹,Met(O₂)¹¹]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar⁹,Met(O₂¹¹]substance P-induced hypotension in dogs (ED₅₀ = 3 μg/kg i.v., bronchoconstriction in guinea-pig (ED₅₀ = 42 μg/kg i.v.) and plasma extravasation in rats (ED₅₀ = 7 μg/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED = 0.2 μg/kg i.v.).     

Opioid activity of sendide, a tachykinin NK1 receptor antagonist

Sendide, a tachykinin NK1 receptor antagonist, was tested for antagonism against scratching, biting and licking responses elicited by intrathecal (i.t.) injections of various tachykinin receptor agonists, N-methyl-D-aspartate (NMDA), somatostatin and bombesin, in mice. Tachykinin NK1 receptor agonists, substance P, physalaemin and septide, produced a characteristic behavioural response, consisting of scratching, biting and licking. The substance P-induced response was reduced by small doses (0.0625-1.0 pmol) of sendide in a dose-dependent manner. The behavioural response elicited by other tachykinin NK1 receptor agonists, physalaemin and septide, was also reduced significantly by a small dose (1.0 pmol) of sendide. The inhibitory effect of sendide (1.0 pmol) was not affected by pretreatment with the opioid receptor antagonist, naloxone, at doses up to 4.0 mg/kg. Higher doses of sendide were needed to reduce the behavioural response to neurokinin A, a tachykinin NK2 receptor agonist, neurokinin B, a tachykinin NK3 receptor agonist and eledoisin, a tachykinin NK2/NK3 receptor agonist. Pretreatment with naloxone (2.0 mg/kg, i.p.) significantly antagonized sendide (1024 pmol)-induced inhibition of the behavioural responses to neurokinin A, neurokinin B and eledoisin. The behaviours elicited by i.t. injection of NMDA, somatostatin or bombesin were also reduced by a higher dose (1024 pmol) of sendide and this sendide effect was reversed by naloxone. These findings suggest that sendide at higher doses may possess opioid activity in addition to an antagonistic action at tachykinin NK1 receptors in the spinal cord.     

Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK1 receptor antagonist

1. The effects of {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171, a selective tachykinin NK₁ receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet.
2. Animals receiving cisplatin (5.5 mg kg⁻¹, i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0_−15 min), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg⁻¹), whereas experimental animals received a single i.v. administration of {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 (1 ml kg⁻¹) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n=8), 0.3 (n=16) or 1.0 (n=13) mg kg⁻¹. In eight additional piglets, {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 (1 mg kg⁻¹) was administered 15 min before the onset of the delayed phase (T16_−15 min). A further five piglets received {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 (1 mg kg⁻¹) every 6 h throughout the experiment.
3. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0_−15 min, and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0_−15 min with {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 1 mg kg⁻¹, eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 (1 mg kg⁻¹) at T16_−15 min exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171.
4. These results demonstrate the long-lasting anti-emetic effects of {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171, and confirm the key role of substance P within the emetic reflex.

     

The anxiolytic-like activity of GR159897, a non-peptide NK2 receptor antagonist,in rodent and primate models of anxiety

The non-peptide NK₂ receptor antagonist, GR159897, was evaluated in two putative models of anxiety, the mouse light-dark box and the marmoset human intruder response test. Effects were compared to the structurally dissimilar NK₂ antagonist, (±) SR48968 and the benzodiazepines, diazepam and chlordiazepoxide. GR159897 (0.0005–50 µg/kg SC) caused significant and dose-dependent increases in the amount of time mice spent in the more aversive light compartment of the light-dark box, with no effect on locomotor activity. (±)SR48968 (0.0005–0.5 µg/kg SC) and diazepam (1–1.75 mg/kg SC), also increased time spent in the light compartment, without effect on locomotor activity. In the marmoset human intruder response test, GR159897 (0.2–50 µg/kg SC) significantly increased the amount of time marmosets spent at the front of the cage during confrontation with a human observer (threat). Similar effects were produced by (±)SR48968 (10–50 µg/kg SC) and chlordiazepoxide (0.3–3.0 mg/kg SC). These results provide further evidence, in both rodent and primate species, for the ability of NK₂ antagonists to restore behaviours which have been suppressed by novel aversive environments. Such effects indicate that NK₂ antagonists may have anxiolytic activity.     

(+/-)-CP-96,345, a selective tachykinin NK1 receptor antagonist, has non-specific actions on neurotransmission.

1. The non-specific effects of the non-peptide tachykinin receptor antagonist (+/-)-CP-96,345, were assessed in several smooth muscle-nerve preparations. The preparations were the iris sphincter muscle of the rabbit and the taenia coli, vas deferens and seminal vesicle of the guinea-pig. 2. (+/-)-CP-96,345 concentration-dependently inhibited the electrically evoked, tachykinin-mediated contractile responses of the iris sphincter and the taenia coli. The pIC50 values were 5.4 +/- 0.2 (mean +/- s.e.mean) and 5.7 +/- 0.08 respectively. 3. (+/-)-CP-96,345 also inhibited non-tachykinin-mediated contractile responses to electrical stimulation of the iris sphincter, taenia coli, vas deferens and seminal vesicle. The pIC50 values were 4.3 +/- 0.02, 4.8 +/- 0.03, 4.7 +/- 0.02 and 4.4 +/- 0.05 respectively. These values differ significantly from the pIC50 values of the inhibition of the tachykinin-mediated response in the iris sphincter and taenia coli. 4. (+/-)-CP-96,345 was without effect on carbachol- and noradrenaline-evoked contractions of the iris sphincter but inhibited carbachol- and prostaglandin F2 alpha (PGF2 alpha)-evoked contractions of the taenia coli. 5. We suggest that (+/-)-CP-96,345, apart from its NK1 receptor blocking activity, induces non-specific suppression of neurotransmission, exerted at both pre- and post-junctional sites.     

The tachykinin NK1 receptor in the brain: pharmacology and putative functions.

After its discovery in 1931, substance P (SP) remained the only mammalian member of the family of tachykinin peptides for several decades. Tachykinins thus refer to peptides sharing the common C-terminal amino acid sequence Phe-X-Gly-Leu-Met x NH2. In recent years the family of mammalian tachykinins has grown with the isolation of two novel peptides from bovine and porcine central nervous system (CNS), neurokinin A and neurokinin B. In parallel with the identification of multiple endogenous tachykinins several classes of tachykinin receptors were discovered. The receptors described so far are named tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK1 receptor, respectively. The present review focuses on the pharmacology and putative function of tachykinin NK1 receptors in brain. The natural ligand with the highest affinity for the tachykinin NK1 receptor is SP itself. The C-terminal sequence is essential for activity, the minimum length of a fragment with reasonable affinity for the tachykinin NK1 receptor is the C-terminal hexapeptide. A rapid advance of knowledge was caused by development of non-peptidic tachykinin NK1 receptor antagonists. This area is under rapid development and a variety of different chemical classes of compounds are involved. Species-dependent affinities of tachykinin NK1 receptor antagonists reveal two clusters of compounds, targeting the tachykinin NK1 receptor subtype found in guinea pig, human or ferret or the one in rat or mouse, respectively. The most recently developed compounds are highly selective, enter the brain and are orally bioavailable. Distinct behavioural effects in experimental animals suggest the involvement of tachykinin NK1 receptors in nociceptive transmission, basal ganglia function or anxiety and depression. Recent clinical trials in man showed that tachykinin NK1 receptor antagonists are effective in treating depression and chemotherapy-induced emesis. Therefore, it is well possible that tachykinin NK1 receptor antagonists will be clinically used for treatment of specific CNS disorders within a short period of time.     

Antiemetic effect of a tachykinin NK1 receptor antagonist GR205171 on cisplatin-induced early and delayed emesis in the pigeon

Cisplatin (4 mg/kg, i.v.) induced both early emesis, which appears within the first 8-h period, and delayed emesis, which appears between 8 and 48 h after its administration to pigeons. GR205171 ([(2S-cis)-N-((2-methoxy-5(5-(trifluoromethyl)-1H-tetrazol-1-yl)-phenyl) methyl)-2-phenyl-3-piperidinamine dihydrochloride]) administered intramuscularly (1-10 mg/kg) reduced significantly the number of emetic response to cisplatin: this reduction was 60-81% (P < 0.05) for early emesis and 48-64% (P < 0.05) for the delayed response. Intracerebroventricularly administered GR205171 (30 microg/kg) also reduced the number of emetic responses: 53% (P < 0.05) in early emesis and 88% (P < 0.05) in the delayed response. However, the latency time to the first emesis was not affected by GR205171. Direct injection of cisplatin (10 microg/kg) into the fourth ventricle produced emesis, which was reduced by GR205171 administered via the peripheral or central route. Substance P-immunoreactive fibres were distributed throughout the dorsal vagal complex. These results suggest that the antiemetic effect of GR205171 on both emetic responses to cisplatin acts on a central site, and that the onset of the emetic response may be mediated partly via GR205171-insensitive mechanisms.     

Discovery of a new series of potent and selective linear tachykinin NK2 receptor antagonists

Starting from 1 (MEN14268), a selective tachykinin NK2 receptor antagonist with an interesting in vitro pharmacological profile, a family of numerous antagonists was obtained through an optimization process focused on iterated structural modifications. The effects of the introduction of a wide variety of substituents on the lipophilic aromatic part of the molecule and the modulation of the structural constraint through the insertion of different achiral alpha,alpha-dialkylamino acids were investigated. In particular, aromatic and benzofused heteroaromatic moieties were introduced at the pseudo-N-terminal residue to replace the 2-benzothiophene moiety, and a systematic investigation of the best positioning of substituents onto the aromatic platform was reported for the benzothiophene core. Studies on the modulation of the length and the rigidity of the hydrophilic pseudo-C-terminal pendant are presented. Many heteroaliphatic groups are well tolerated by the receptor in this part of the ligand. The product 48f (MEN15596), bearing a methyl substituent on the benzothiophene and a tetrahydropyranylmethylpiperidine pendant, was finally selected for its good in vivo activity after intravenous, intraduodenal, and oral administration in guinea pigs.     

Metabolism,pharmacokinetics and excretion of a potent tachykinin NK1 receptor antagonist (CP-122,721) in rat: Characterization of a novel oxidative pathway

The metabolism, pharmacokinetics and excretion of a potent and selective substance P receptor antagonist, (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzlamino)-2-phenylpiperidine, CP-122,721, have been studied in rat following oral administration of a single dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was 84.1?±?1.1% for male rat and 80.9?±?2.7% for female rat. Approximately 81% of the administered radioactivity recovered in urine and faeces were excreted in the first 72?h. Absorption of CP-122,721 was rapid in both male and female rat, as indicated by the rapid appearance of radioactivity in plasma. The plasma concentrations of total radioactivity were always much greater than unchanged drug, indicating early formation of metabolites. CP-122,721 t_1/2 was 3.1 and 2.2?h for male and female rat, respectively. The plasma concentrations of CP-122,721 reached a peak of 941 and 476?ng?ml^?1 for male and female rat, respectively, at 0.5?h post-dose. Based on AUC_0–tlast, only 1.5% of the circulating radioactivity was attributable to unchanged drug (average of male and female rats) and the balance, approximately 98.5% of the plasma radioactivity was due to metabolites. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety and aliphatic oxidation at the benzylic position of the trifluoromethoxy anisole moiety. In addition, a novel oxidative metabolite resulting from ipso substitution by the oxygen atom and trifluoromethoxy elimination followed by glucuronide conjugation was also identified.     

Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP-96,345.

The affinity of the non-peptide antagonist CP-96,345 for tachykinin NK1 receptors has been estimated in a range of species by use of both radioligand binding and functional assays. CP-96,345 was 30-120 fold less active at NK1 receptors in rat and mouse than in the other species examined, including man. These results demonstrate the existence of species variations in NK1 receptors.     

Metabolism, pharmacokinetics and excretion of a potent tachykinin NK1 receptor antagonist (CP-122,721) in rat: characterization of a novel oxidative pathway

The metabolism, pharmacokinetics and excretion of a potent and selective substance P receptor antagonist, (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzlamino)-2-phenylpiperidine, CP-122,721, have been studied in rat following oral administration of a single dose of [14C]CP-122,721. Total recovery of the administered dose was 84.1+/-1.1% for male rat and 80.9+/-2.7% for female rat. Approximately 81% of the administered radioactivity recovered in urine and faeces were excreted in the first 72 h. Absorption of CP-122,721 was rapid in both male and female rat, as indicated by the rapid appearance of radioactivity in plasma. The plasma concentrations of total radioactivity were always much greater than unchanged drug, indicating early formation of metabolites. CP-122,721 t1/2 was 3.1 and 2.2 h for male and female rat, respectively. The plasma concentrations of CP-122,721 reached a peak of 941 and 476 ng ml-1 for male and female rat, respectively, at 0.5 h post-dose. Based on AUC0-tlast, only 1.5% of the circulating radioactivity was attributable to unchanged drug (average of male and female rats) and the balance, approximately 98.5% of the plasma radioactivity was due to metabolites. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety and aliphatic oxidation at the benzylic position of the trifluoromethoxy anisole moiety. In addition, a novel oxidative metabolite resulting from ipso substitution by the oxygen atom and trifluoromethoxy elimination followed by glucuronide conjugation was also identified.