Expedited discovery of second generation NK-1 antagonists: identification of a nonbasic aryloxy substituent.

Solution-phase, parallel-synthesis techniques were used to optimize a series of nonbasic NK-1 antagonists, resulting in the identification of (R)-26, an orally bioavailable compound with subnanomolar potency.

Dose-response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy.

Lanepitant is effective in the formalin analgesic model suggesting efficacy in painful neuropathy. This study was designed to evaluate the dose-response effect of lanepitant in patients with daily moderate to severe, bilateral, distal neuropathic pain. After a 1-to 3-week lead-in period, patients were randomly allocated to double-blind, parallel treatment with lanepitant 50 mg daily (n = 27), 100 mg daily (n = 27), 200 mg twice daily (n = 13), or placebo (n = 26) over 8 weeks. Patients reported average daytime pain and average nighttime pain intensity. Plasma concentrations and amount of adjunctive analgesic medication were obtained at all visits after baseline. Patient global evaluation and clinician global impression were obtained at weeks 3 and 8. Safety was assessed by adverse events, vital signs, laboratory analytes, and electrocardiogram. No dosage of lanepitant differed significantly from placebo. Efficacy did not increase with lanepitant dosage, and higher plasma concentrations were no more effective than lower plasma concentrations. The adverse event diarrhea was more frequent for lanepitant-treated patients. Although well tolerated, lanepitant was ineffective in relieving pain of diabetic neuropathy.

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Regulation of amyloid precursor protein processing by Abeta in human glioma cells.

Amyloid precursor protein (APP) is cleaved to neurotoxic/proinflammatory amyloid beta protein (Abeta) or to the neuroprotective secreted alpha-APPs. A balance in APP metabolism may influence the outcome between toxicity and protection to central nervous system (CNS) neurons in Alzheimer's disease. Treatment of U-373 MG astrocytoma cells with aggregated Abeta (1-40) decreases APP secretion into the medium to 10-30% of control values. This decreased secretion appears to be specific for APP since Abeta treatment causes an approximately 2-fold increase in interleukin-8 (IL-8) secretion. Abeta treatment also causes a 4- to 9-fold increase in total cell-associated APP. This increase is due to cellular retention of alpha secretase-cleaved APP and a 2-fold increase in mature full-length APP. These data suggest that deposition of aggregated Abeta may contribute to Alzheimer's-associated neurotoxicity by altering the metabolism of the APP protein. Abeta may exert harmful effects by decreasing the secretion of neuroprotective or neurotrophic APP and, in addition, by increasing intracellular full-length APP; thereby providing increased substrate for generation of amyloidogenic peptide within astrocytes.

Study of the analgesic effect of lanepitant in patients with osteoarthritis pain.

OBJECTIVE: Lanepitant selectively blocks substance P binding to the neurokinin-1 receptor, preventing neurogenic inflammation and pain transmission. Substance P is present in synovial fluid and in excess in cerebral spinal fluid. We investigated the effect of lanepitant on pain caused by osteoarthritis to evaluate the role of neurokinin-1 blockade. METHODS: Outpatients (n = 214) with moderate to severe lower-limb osteoarthritis pain were treated for 3 weeks in a parallel, randomized double-blind study with initial doses of 20, 60, 200, or 600 mg lanepitant, 375 mg naproxen, or placebo, followed by 10, 30, 100, or 300 mg lanepitant twice a day, 375 mg naproxen twice a day, or placebo twice a day in the multiple-dose period. Pain intensity, pain relief, patient global impression, and adjunctive analgesic use were compared across treatments. Safety was evaluated with adverse events, vital signs, and laboratory assessments. RESULTS: There was no statistically significant difference in efficacy or safety across treatments for the initial dose assessment. After 1 week of therapy, naproxen was statistically significantly (P < .05) better than placebo and lanepitant in reducing average pain. During the second and third weeks of therapy, patients receiving naproxen continued to have statistically significantly (P < .05) less pain than those receiving placebo or lanepitant despite using significantly less adjunctive analgesic medication. There were no statistically significant differences in rates of discontinuation across treatments. Lanepitant treatment was associated with diarrhea, whereas naproxen treatment was associated with gastric discomfort. There were no clinically relevant changes in vital signs or laboratory analytes for any of the treatments. CONCLUSION: Lanepitant was ineffective in relieving osteoarthritis pain, possibly because neurokinin-1 binding of substance P does not play a significant role in osteoarthritis pain or because lanepitant fails to adequately penetrate the blood-brain barrier to affect central pain perception.

Human amylin stimulates inflammatory cytokine secretion from human glioma cells.

Chronic neurodegeneration in the brains of Alzheimer's disease (AD) patients may be mediated, at least in part, by the ability of amyloid beta (Abeta) to exacerbate inflammatory pathways in a conformation-dependent manner. In this regard, we previously reported that the Abeta-peptide-mediated potentiation of inflammatory cytokine secretion from interleukin-1beta (IL-1beta)-stimulated human astrocytoma cells was conformation dependent. Other amyloidogenic peptides, such as human amylin, which display similar conformation-dependent neurotoxic effects, may also elicit inflammatory cytokine secretion from glial cells. To test this hypothesis, we compared human and rat amylin for the effects on cytokine production in U-373 MG human astrocytoma cells. Human amylin alone stimulated U-373 MG cells to secrete IL-6 and IL-8 in a concentration-dependent manner with maximum effects seen at 10-25 microM peptide. In addition, human amylin markedly potentiated IL-1beta-stimulated cytokine production with a similar concentration dependence. In contrast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1beta. Aging human amylin resulted in diminished cytokine secretion, probably due to the formation of large, less active aggregates. In agreement with our previous studies using Abeta, extracellular Ca(2+) was necessary for human amylin stimulation of cytokine secretion. Our data suggest that amyloidogenic peptides promote cytokine secretion through similar beta-sheeted secondary-structure- and extracellular-Ca(2+)-dependent mechanisms.

Substance P regulates PTH secretion through the neurokinin-1 receptor.

The primary regulator of PTH secretion is serum ionized Ca(2+); however, neuropeptide-containing nerve fibers have been localized to the parathyroid gland. The purpose of this study was to determine whether or not substance P (SP) regulates PTH secretion. In dispersed porcine parathyroid cells, SP reversibly inhibited 0.5 mM CaCl(2)-induced PTH secretion (IC(50) = 0.29 nM) and had no effect at CaCl(2) concentrations of 1.5 mM and greater. At 0.5 mM CaCl(2), treatment with a NK-1 selective receptor agonist resulted in a concentration-dependent decrease in PTH secretion (IC(50) = 0.21 nM). In contrast, NK-2 and NK-3 receptor agonists were approximately 100-fold less active than SP or the NK-1 receptor selective agonist. An enantiospecific reversal of the effects of SP on PTH secretion was observed with LY306740, a potent selective NK-1 receptor antagonist (K(i) = 0.125 nM). In porcine parathyroid cells, expression of mRNA for the NK-1 receptor was observed using RT-PCR. In summary, a novel neuroendocrine pathway is described whereby the neuropeptide, SP, regulates PTH secretion through NK-1 receptors.

Regulation of cytokine secretion and amyloid precursor protein processing by proinflammatory amyloid beta (A beta).

Neurodegenerative processes in Alzheimer's disease (AD) are thought to be driven, in part, by the deposition of amyloid beta (A beta), a 39-43-aminoacid peptide product resulting from an alternative cleavage of amyloid precursor protein (APP). In addition to its neurotoxic properties, A beta may influence neuropathology by stimulating glial cell cytokine and acute phase protein secretion in affected areas of the brain (e.g., cortex, hippocampus). Using an in vitro human astrocyte model (U-373 MG astrocytoma cells), the effects of A beta treatment on acute phase protein (APP and alpha-1-antichymotrypsin [alpha 1-ACT]) and interleukin-8 (IL-8) were examined. U-373 MG cells secreted increased levels of alpha 1-ACT and neurotrophic/neuroprotective alpha-cleaved APP (alpha APP) after exposure to interleukin-1 beta (IL-1 beta) for 24 hours. A beta treatment resulted in a similar, but modest increase in alpha 1-ACT secretion, a two- to threefold stimulation of IL-8 production, and, conversely, a profound reduction in the levels of secreted alpha APPs. A beta inhibited alpha APP secretion by U-373 MG cells in a concentration- and conformation-dependent manner. Moreover, the reduction in alpha APP secretion was accompanied by an increase in cell-associated APP. Another proinflammatory amyloidogenic peptide, human amylin, similarly affected APP processing in U-373 astrocytoma cells. These data suggest that A beta may contribute to Alzheimer's-associated neuropathology by lowering the production of neuroprotective/neurotrophic alpha APPs. Moreover, the concomitant increase in cell-associated APP may provide increased substrate for the generation of amyloidogenic peptides within astrocytes.

[3H]LY303870, a novel nonpeptide radioligand for the NK-1 receptor.

We synthesized a potent and selective antagonist radioligand for the neurokinin (NK)-1 receptor and characterized its binding to guinea pig striatal membranes. (R)-N-[2-[Acetyl[3H3][(2-methoxyphenyl)-methyl]amino]- 1-(1H-indol-3-ylmethyl) ethyl][1,4'-bipiperidine]- 1'-acetamide ([3H]LY303870) binds to a single class of sites with an equilibrium KD of 0.22 nM and a Bmax of 723 fmol/mg of protein. Unlabeled LY303870 potently inhibited the binding with an IC50 of 0.56 nM, whereas the less active (S)-enantiomer (LY306155) was substantially less potent. The nonpeptide NK-1 antagonists (+/-)-CP96,345 and (+/-)-RP 67580 had IC50 values of 0.74 and 49 nM, respectively. Substance P (SP) was also a potent inhibitor with with an IC50 of 3.1 nM. The inhibition by SP could be separated into two components: a high-affinity component with a Ki of 0.53 nM and a lower-affinity component with a Ki of 155 nM. Addition of 100 microM guanylyl 5'-imidodiphosphate [Gpp(NH)p] in the incubation increased the relative amount of the low-affinity agonist state of the receptor. Consistent with the antagonist properties of LY303870, the dissociation rate of [3H]-LY303870 was not changed by the presence of 100 microM Gpp(NH)p. The distribution of [3H]LY303870 binding sites in the guinea pig brain closely matched the distribution of NK-1 receptors labeled by [3H]SP. Therefore, [3H]LY303870 is a potent and selective antagonist radioligand for NK-1 receptors in guinea pig brain. In addition, regulation of NK-1 agonist affinity by guanine nucleotides is similar to that seen for monoaminergic receptors.

3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists.

Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC50's = 100 pM to > 5 microM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg6,Sar9,Met(O2)11]- substance P 6-11 (Ac-Sar9)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID50 = 91 ng/kg) and have a long duration of action (> 8 h at 1 micrograms/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.

Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist.

LY303870 [(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane] is a new, potent and selective nonpeptide neurokinin-1 (NK-1) receptor antagonist. LY303870 bound selectively and with high affinity to human peripheral (Ki = 0.15 nM) and central (Ki = 0.10 nM) NK-1 receptors. LY303870 inhibited [125I]substance P (SP) binding to guinea pig brain homogenates with similar affinity; however, it had approximately 50-fold lesser affinity for rat NK-1 sites. The less active enantiomer, LY306155 [(S)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]-propane], was 1,000- to 15,000-fold less potent in all the species examined. LY303870 antagonized in vitro NK-1 receptor effects as demonstrated by blockade of SP-stimulated phosphoinositide turnover in UC-11 MG human astrocytoma cells (Ki = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytoma cells (Ki = 5 nM). In addition, LY303870 inhibited SP-induced rabbit vena cava contractions (pA2 = 9.4) with high (50,000-fold) selectivity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 inhibited [Sar9,Met(O2)11]-SP induced guinea pig bronchoconstriction (ED50 = 75 micrograms/kg i.v.) and pulmonary microvascular leakage in the bronchi (ED50 = 12.8 micrograms/kg i.v.) and trachea (ED50 = 18.5 micrograms/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 receptor antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.

Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells.

Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged A beta modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1 beta (IL-1 beta), aged, but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged A beta did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1 beta-induced cytokine release was potentiated by A beta-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A beta to exacerbate inflammatory pathways in a conformation-dependent manner.

Cyclosporin A is a substance P (tachykinin NK1) receptor antagonist.

The immunosuppressive cyclic undecapeptide, cyclosporin A, inhibited the binding of [125I]substance P to tachykinin NK1 receptors expressed by human IM-9 lymphoblastoid cells, U-373 MG human astrocytoma cells and guinea pig lung parenchyma with IC50 values of 425 +/- 58, 783 +/- 180, and 784 +/- 163 nM respectively. The dihydro derivative of cyclosporin A (dihydro-cyclosporin A) was an equally effective inhibitor, but the O-acetylated derivative (cyclosporin A-OAc) was 3-4 fold less potent. The cyclosporin compounds also inhibited [125I]neurokinin A binding to human NK2 receptors with potencies slightly less than at NK1 sites. In contrast, they were 8-20-fold less effective inhibitors of [125I]MePhe7-neurokinin B binding to guinea pig NK3 receptors (p < 0.001). Thus, the cyclosporin A compounds showed selectivity for NK1 and NK2 receptors. The structure-activity pattern for the effects of cyclosporin A compounds at tachykinin receptors differs from the pattern previously described for their immunosuppressive activity. All three compounds inhibited substance P induced interleukin-6 (IL-6) secretion from U-373 MG astrocytoma cells with potencies similar to their NK1 receptor binding affinities. In addition, cyclosporin A blocked substance P induced phosphatidylinositol (PI) turnover in U-373 MG cells without blocking the corresponding response to histamine. This novel pharmacological profile of the cyclosporin A compounds as NK1 receptor antagonists does not appear to correlate with other known in vitro cyclosporin A functions.

Interleukin-6 secretion from human astrocytoma cells induced by substance P.

Functional NK-1 (substance P) receptors have been demonstrated previously on astrocytes from primary newborn rat brain cultures and human astrocytoma cells lines by specific [125I]-Bolton Hunter substance P (SP) binding and by SP-induced phosphoinositol turnover. In addition, these cells have been shown to release cytokines upon stimulation with interleukin-1 (IL-1) and lipopolysaccharide (LPS). Since SP has also been shown to induce cytokine release from rat glial cells, this neuropeptide may contribute to the pathophysiology of neuronal inflammation in humans by stimulating cytokine production in the brain. We, therefore, explored whether SP could induce U-373 MG human astrocytoma cells, via specific NK-1 receptor activation, to secrete interleukin-6 (IL-6), a cytokine implicated as a key mediator of immune and inflammatory responses. SP stimulated IL-6 production in a concentration-dependent manner with an MC50 (concentration inducing 50% of the maximum response) of 45 nM. IL-6 was detected in the cell culture supernatant fluids 2 h post stimulation and secretion peaked at 12 h. SP induced IL-6 secretion was not mediated by IL-1 since neutralizing anti-IL-1 (alpha and beta) antibody treatment had no effect on the SP response. The selective NK-1 receptor agonist, [Sar9, Met(O2)11]-SP, was comparably effective to SP in stimulating IL-6 secretion; however, selective NK-2 and NK-3 receptor agonists were 250-500-fold less effective. In addition, the non-peptide NK-1 receptor antagonist, (+/-)CP-96,345, inhibited SP (Ki = 4 nM), but not IL-1-induced IL-6 release. These selectivity and specificity studies confirmed the presence of functional NK-1 type receptors linked to IL-6 release. The results of this study support a role for SP as a modulator of immune and/or inflammatory processes in the human CNS.

Use of non-peptide tachykinin receptor antagonists to substantiate the involvement of NK1 and NK2 receptors in a spinal nociceptive reflex in the rat.

Non-peptide antagonists of the NK1 and NK2 receptors were tested as inhibitors of the reaction time in the rat tail-flick and on the decrease of reaction time induced by the intrathecal injection of the NK1 receptor selective agonist [Sar9,Met(O2)11]SP or of the NK2 selective agonist NKA-(4-10). The decrease in reaction time produced by the NK1 agonist lasted less than 11 min while that evoked by the NK2 agonist persisted 26 min after injection. When given intrathecally, CP-96,345 and its chloro analog, Cl-CP, blocked dose-dependently both the behavioral responses and the decreases of reaction time induced by 6.5 nmol of [Sar9,Met(O2)11]SP while they failed to modify the hyperalgesic response to 6.5 nmol NKA-(4-10); CP-96,345 was found more potent than Cl-CP and was also active as an antagonist when given intravenously. In contrast, SR 48968 (6.5 and 65 nmol) blocked the NKA-(4-10)-induced decreases in reaction time and was inactive against the hyperalgesic effect of [Sar9,Met(O2)11]SP. The three antagonists blocked in a reversible manner, were inactive on their own on reaction time and non-toxic. The results indicate that the non-peptide CP-96,345 readily crosses the blood brain barrier and acts as a selective antagonist on spinal NK1 receptors, while SR 48968 is selective on NK2 receptors in the rat spinal cord. Hence, CP-96,345 and SR 48968 highlight a functional role of NK1 and NK2 receptors in spinal sensory neurotransmission.

beta-Amyloid peptide in vitro toxicity: lot-to-lot variability.

beta A4 peptide (beta AP) accumulates in amyloid plaques of Alzheimer's disease and may contribute to neuronal degeneration. Conflicting observations have been reported regarding the direct in vitro and in vivo neurotoxicity of beta AP. We have assessed in vitro beta AP toxicity in high density primary rat hippocampal cultures and found marked lot-to-lot differences in the neurotoxic properties of beta AP. One lot of beta AP from a commercial supplier resulted in significant direct neurotoxicity at 10 microM, while 2 other lots from the same supplier were essentially nontoxic. Three additional lots of beta AP from unrelated sources were also nontoxic at 10 microM. Initial biochemical characterization has not yet revealed any marked differences among the various lots of beta AP. Low levels of endotoxin (ca., 1 EU/ml) were detected in several beta AP preparations but did not correlate with neurotoxicity. Our observation that lot-to-lot variability of beta AP occurred even under identical in vitro culture conditions may account for part of the present controversy in this area.

Retinoic acid potentiates interleukin-1- and fibroblast growth factor-induced human synovial fibroblast proliferation.

All trans-retinoic acid (ATRA) and related compounds, at concentrations ranging from 10(-8) to 10(-6) M, augmented the proliferation of human synovial fibroblasts (HSN) stimulated by human interleukin-1 alpha or -beta (IL-1 alpha, IL-beta) and both the acidic and basic forms of fibroblast growth factor (FGFa, FGFb). In contrast, ATRA had no effect on human tumor necrosis factor alpha (TNF alpha)-induced HSN proliferation. The potentiation of HSN proliferation was completely dependent on the presence of IL-1 or FGF since HSN were unresponsive to ATRA alone. The mechanism by which ATRA enhances IL-1-induced HSN proliferation does not appear mediated by changes in the affinity or number of IL-1 receptors expressed by HSN; however, treatment with dexamethasone (DEX, 10(-6)M) resulted in a twofold increase in IL-1 receptor number. ATRA inhibited both IL-1 beta- and TNF alpha-induced secretion of prostaglandin-E2 (PGE2), a potent feedback inhibitor of cytokine-stimulated HSN proliferation. However, the synergistic effect of ATRA on IL-1- or FGF-induced proliferation did not appear related to the secretion of cyclooxygenase products since ATRA had no effect on TNF alpha-induced HSN proliferation and indomethacin was included in all HSN proliferation experiments. The results of this study suggest that ATRA may contribute to the pathology of chronic arthritic disease by potentially causing increased growth of the joint-destroying pannus.

Selectivity and specificity of new, non-peptide, quinuclidine antagonists of substance P.

Two members of a new class of non-peptide antagonists of substance P, (+-)-cis-3-(2-methoxybenzylamino)-2-benzhydrylquinuclidine [(+/-)-CP-96,345; I] and (+-)-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine [II], were tested for their ability to antagonize neurokinin-induced contractions of the rabbit cava and jugular veins (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3 system). Compound 1 is the most potent NK-1 receptor antagonist identified until now; its apparent affinity (pA2 = 9.52) is at least two log units higher than those of other NK-1 antagonists. Compound II is less active. Both compounds have been found to be almost inactive as NK-2 and NK-3 antagonists and should, therefore, be considered as selective for the NK-1 receptor. The new compounds have no direct myotropic effects and are specific for neurokinin (NK-1) receptors since they do not affect the myotropic effects of angiotensin, noradrenaline and bradykinin in the rabbit cava and jugular veins.