Non-peptide NK1 Antagonists Research Articles

NK-1 antagonist CP99994 inhibits stress-induced mast cell degranulation in rats

Mast cells are implicated in stress-induced inflammatory skin diseases such as psoriasis. Mechanisms of stress-induced mast cell degranulation however, are not entirely clear. Here we explore the role of activation of a Substance P (SP) receptor (NK-1) on mast cell degranulation upon exposure to stress in rats. A specific nonpeptide NK-1 antagonist, CP99994 was used to treat the rats either peripherally or intracerebroventricularly. Because increased SP activity in the brain may mediate the stress response, we also examined cutaneous mast cell degranulation after central injection of SP. Stress, as well as SP injected centrally, increased mast cell degranulation. Both central and peripheral injection of CP99994 prevented stress-induced mast cell degranulation. Surprisingly, the combination of stress with SP decreased mast cell degranulation, suggesting that high levels of SP may counteract the stress responses. Results in this animal model suggest that NK-1 antagonists may be used therapeutically to treat stress-induced inflammatory skin diseases; however, drug doses should be chosen carefully.

Medicinal chemistry of selective neurokinin-1 antagonists.

The study of tachykinin NK1 (substance P) receptor antagonists has emerged as a field of great promise due to accumulating evidence that NK1 antagonists offer possible new treatment options in therapeutic areas ranging from pain, emesis, and pulmonary disorders to depression and anxiety. It is hoped that the unique mechanism of action of these agents, which involves modulation of effects mediated by the interaction of the neuropeptide substance P with it's G-protein coupled receptor, will provide improvements over existing therapies. For this reason many pharmaceutical companies are engaged in intense research programs with the goal of bringing safe and effective new drugs to the market. To date a wealth of diverse NK1 antagonists have been discovered, several of which have been evaluated in clinical trials. Despite rich structural diversity in this area of medicinal chemistry a number of structural features are commonly shared amongst otherwise unrelated antagonists. This theme and others are covered with the aim of conveying recent successful approaches to the discovery of potent and selective nonpeptide NK1 antagonists. This review focuses mainly on reports appearing in the year 2001 and the first half of 2002.

An open assessment of the safety and efficacy of venlafaxine in mild to moderate and in severe depression in usual care settings in Hungary

The locomotor activity (LMA) response induced after infusion of selective neurokinin (NK) agonists into the cell body (A10) and a terminal region of the mesolimbic pathway of the rat was investigated. Infusion of the NK1 receptor-selective agonist, GR73632, into the ventral tegmental area (VTA: A10) or the nucleus accumbens (NAS) significantly and dose-dependently increased basal LMA. Agonists selective for the NK2 and NK3 receptors, GR64349 and senktide respectively, had no effect on LMA after intra-NAS infusion. The LMA induced by GR73632 is mediated via dopamine (DA) since the response was abolished by haloperidol. From these studies it would appear that the elevated LMA reported previously after VTA or NAS administration of substance P probably occurs via NK1 receptors. Such data supports the notion that endogenous NKs are likely to be important in modulating the mesolimbic DA pathway and, as a consequence, compounds which antagonise their effects could be useful for the treatment of disorders associated with this system. However, simultaneous infusion of the NK1 agonists, ±CP-96, 345 and its analogue CPQ, into the VTA did not attenuate the LMA induced after intra-VTA infusion of GR73632. Co-infusion of the NK1 antagonist CPQ, but not±CP-96,345, attenuated the LMA response induced by GR73632 in the NAS. The apparent poor susceptibility of these responses to blockade by the recently developed non-peptide NK1 antagonists was unexpected but may reflect their poor affinity for the rat variant of the NK1 receptor. Further advances in the chemistry of NK1 antagonists are now required to confirm the apparent importance of NK1 receptor activation in the control of the mesolimbic DA pathway.

Nonadrenergic noncholinergic vasodilation of guinea pig pulmonary arteries is mediated by nitric oxide

Nonadrenergic noncholinergic (NANC) mediated vasodilation may contribute to the maintenance of low pulmonary vascular tone. The NANC neurotransmitters, nitric oxide (NO) and the sensory neuropeptides, substance P and calcitonin gene related peptide (CGRP), were investigated as possible mediators of NANC vasodilation in guinea pig pulmonary arteries. Fresh guinea pig pulmonary artery rings, with and without an intact endothelium, were mounted in organ baths containing Krebs solution and precontracted with the prostaglandin F2alpha analogue U44069. In both endothelium-intact and denuded vessels, electrical field stimulation (1-12 Hz) in the presence of guanethidine and atropine resulted in a frequency-dependent vasodilation. The peptide fragment hCGRP8-37, a competitive antagonist of the CGRP receptors, the peptide fragment NK1 antagonist SP4-11, and the nonpeptide NK1 antagonist RP67580 had no effect on NANC vasodilation. In both endothelium-intact and denuded vessels, N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, inhibited NANC vasodilation, an effect that was reversible with L-arginine. We conclude that NANC vasodilation in guinea pig pulmonary arteries is mediated predominantly through NO activity.

Effects of RPR 100893, a potent NK1 antagonist, on the jaw-opening reflex in the guinea pig

RPR 100893 appears as a new potent NK1 selective non-peptide antagonist both in vitro and in vivo, and exhibits high affinity for guinea pig and human NK1 receptor [M. Tabart, J.-F. Peyronel, Synthesis of RPR 100893, prototype of a new series of potent and selective non-peptide NK1 antagonists: the triarylperhydroisoindolols, Bioorg. Med. Chem. Lett., 4 (1994) 673–676.]. Intra-oral administration of RPR 100893 (3, 15, 10, 30 mg/kg) was performed in freely moving guinea pigs during recording of the short- (6–10 ms) and long-latency (18–26 ms) jaw-opening reflex (JOR) elicited by electrical stimulation (0.5 Hz) of the lower incisor tooth pulp. RPR 100893 induced a noticeable and dose-dependent increase of the long-latency reflex thresholds ( P<0.001) but was ineffective on the short-latency responses ( P=0.14). The results suggest that, in guinea pigs, the long-latency JOR requires activation of NK1 receptors, while the earlier reflex component, elicited by activation of periodontal afferents, does not. These NK1 receptors could be located either on JOR interneurons activated by tooth pulp afferents or on digastric motoneurons, receiving the tooth pulp input through a polysynaptic pathway.

Tachykinin receptors mediating non-cholinergic contraction of the guinea-pig isolated main bronchus in response to field stimulation.

1. The primary aim of the present study was to classify the receptors activated by tachykinins released by field stimulation of intramural nerve terminals of the guinea-pig isolated main bronchus by using the novel non-peptide NK1 and NK2 receptor-selective antagonists SR 140333 and SR 48968, respectively. 2. Log concentration-response curves to substance P (SP), the NK1 receptor-selective agonist [Sar9, Met(O2)11]-SP and the NK2 receptor-selective agonist [Nle10]-neurokinin (NK) A(4-10) were constructed in the presence of indomethacin (2 mumol/L) and phosphoramidon (5 mumol/L). Substance P was the least potent of these agonists. 3. In left and right main bronchi, SR 140333 (100 nmol/L) antagonized concentration-related contractions evoked by SP yielding pKB values of 8.02 and 7.68, respectively. SR 140333 (10 nmol/L) antagonized the effects of [Sar9, Met(O2)11]-SP on the left bronchus with a pKB value of 8.04. 4. SR 48968 (100 nmol/L) antagonized the effects of SP yielding pKB estimates of 7.88 (left bronchus) and 7.31 (right bronchus). 5. [Nle10]-NKA(4-10) was more potent in the left than in the right main bronchus. SR 48968 (0.1-10 nmol/L) antagonized the effects of [Nle10]-NKA(4-10) on the left bronchus with pKB estimates of 8.26-10.25. 6. In the presence of indomethacin (2 mumol/L), phosphoramidon (5 mumol/L) and atropine (1 mumol/L), electrical field stimulation (EFS; 30 V, 1 ms, 15 s at 1, 3, 10 and 30 Hz) produced prolonged contractions. SR 48968 (0.1 mumol/L) markedly reduced responses to stimulation, whereas SR 140333 (0.3 mumol/L) caused a small but significant rightward displacement of the log frequency-response curve. In combination, these concentrations of SR 48968 and SR 140333 produced complete inhibition to field stimulation at 10 Hz. 7. These results indicate that: (i) both NK1 and NK2 receptor subtypes are present in the guinea-pig main bronchi with the left bronchus being more sensitive to an NK2 receptor agonist; and (ii) EFS of the main bronchus leads to frequency dependent contractions due to the release of tachykinin(s) that predominantly activate an NK2 receptor.

Inhibition of Ca(2+)-sensitive K+ currents in NG 108-15 cells by substance P and related tachykinins.

1. The whole-cell patch-clamp technique was used to investigate the actions of substance P and other agonists at neurokinin (NK) receptors on voltage-gated K+ and Ca+ channel currents in undifferentiated mouse neuroblastoma x rat glioma NG 108-15 cells. 2. Both substance P (0.3-30 microM) and the NK1 receptor selective agonist GR73632 (10 nM-10 microM) caused concentration-dependent inhibition of K+ currents. GR64349 and senktide (agonists at NK2 and NK3 receptors respectively) also inhibited K+ currents, but only at concentrations which were several orders of magnitude greater than GR73632, suggesting that current inhibition was mediated via NK1 receptors. 3. Substance P and GR73632 were without effect on residual K+ currents recorded in the presence of extracellular Co2+ (4 mM) to abolish the Ca(2+)-sensitive component (IKca) of the K+ current. Ca2+ channel currents, recorded with either Ba2+ or Ca2+ as charge carrier, were unaffected by NK1, NK2 and NK3 receptor ligands. 4. Iontophoretic application of GR73632 produced a current-dependent reduction of K+ currents. In the presence of the non-peptide NK1 antagonists, CP-99,994 and RP67580, and the peptide antagonist, GR82334, the current-response relationship was reversibly shifted to the right. This indicates that the response is mediated by NK1 receptors. 5. Our results indicate that activation of NK1 receptors leads to the selective inhibition of IKca in undifferentiated NG 108-15 cells.

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.

Nitric oxide is a mediator of tachykinin NK3 receptor-induced relaxation in rat mesenteric artery.

1. The mechanism of vasodilatation induced by tachykinin peptides was studied in isolated mesenteric arteries of rats. 2. Senktide, a selective NK3 agonist, elicited potent endothelium-dependent relaxation of arteries precontracted with phenylephrine (10(-5) M), but an NK1 agonist did not. 3. A non-peptide NK3 antagonist, SR 142801, inhibited senktide-induced relaxation. However, a non-peptide NK1 antagonist, CP-96,345, and a peptide-based NK2 antagonist, L-659,877, had no effect on senktide-induced relaxation. 4. N omega-nitro-L-arginine (L-NOARG), a nitric oxide synthesis inhibitor, markedly attenuated the relaxant response to senktide. 5. These results suggest that the endothelium of rat mesenteric arteries possesses tachykinin NK3 receptors, and that NK3 agonist-induced vasodilatation is mediated by release of nitric oxide (NO) from the endothelium.

Pharmacological Characterization of Tachykinin Receptors Controlling Acetylcholine Release from Rat Striatum: An In Vivo Microdialysis Study

The regulation of striatal cholinergic function by tachykinins was examined in urethane-anesthetized rats by using microdialysis. Substance P (0.01-1 microM), [Sar9, Met (O2)11]substance P (1-10 microM), septide (0.1-3 microM), neurokinin (NK) A (0.1-10 microM), and senktide (0.1-10 microM) produced concentration-dependent increases in striatal acetylcholine (ACh) release. Septide was the most potent agonist for inducing release of ACh, whereas the stimulating effect of senktide was less pronounced and more progressive in onset. The response to septide was prevented by intraperitoneal administration of the nonpeptide NK1 antagonist SR 140333 (1-3 mg/kg) but not by the nonpeptide NK2 receptor antagonist SR 48968, indicating that the effect was mediated specifically by NK1 receptors. ACh release caused by NKA was reduced by SR 48968 (1-3 mg/kg) and slightly affected by SR 140333, indicating a principal role for NK2 receptors in the peptide response. The similar efficacy of SR 140333 and SR 48968 in blocking substance P-induced ACh release suggested that the effect of this peptide involves the stimulation of both NK1 and NK2 receptors. Finally, our results indicate that the increase in striatal ACh release induced by the D1 agonist (+)-SKF-38393 (3 microM) may be mediated indirectly through local release of NKA or substance P acting at NK2 receptors.

Section Review—Central &amp; Peripheral Nervous Systems: Tachykinin Antagonists in Development

The literature on tachykinin antagonists published during the second semester of 1994 is reviewed with emphasis on the potential clinical indications for antagonists of the three neurokinin receptor families, namely NK1, NK2 and NK3 . For each therapeutic domain, particular attention is given to the development of adequate experimental animal models needed to evaluate new compounds in vitro and in vivo. Finally, recent developments in the molecular biology of NK1 receptors and design of new non-peptide NK1 antagonists are presented.

Perhydrothiopyranopyrroles derivatives : A novel series of potent and selective nonpeptide NK1 antagonists.

The synthesis of RP 73467, a representative of 4,4-diphenyl perhydrothiopyrano[2,3-c]-pyrroles 1-oxides, a new series of potent and selective nonpeptide NK1 Substance P antagonists, is described.

Effects of FK224, a Novel Cyclopeptide NK1 and NK2 Antagonist, and CP-96,345, a Nonpeptide NK1 Antagonist, on Development and Maintenance of Thermal Hyperesthesia Evoked by Carrageenan Injection in the Rat Paw

The role of tachykinins, such as substance P and neurokinin A, in the development or maintenance of thermal hyperesthesia during inflammation is unclear. In the current study, the authors examined the role of NK1 and NK2 receptors on the thermal hyperesthesia evoked by injection of carrageenan into the rat paw using FK224, a cyclopeptide NK1 and NK2 antagonist, and CP-96,345, a nonpeptide NK1 antagonist. In rats injected with 2 mg carrageenan, the paw withdrawal latency (PWL) for the injected paw was typically 5-6 s less than that for the untreated paw, at 2 h after the carrageenan injection. In the pretreatment study, drugs were administered intravenously or intrathecally 10 min before the carrageenan injection. In the posttreatment study, drugs were administered intravenously or intrathecally 2 h after the carrageenan injection. In the pretreatment study, both intravenous CP-96,345 and intravenous FK224 blocked the development of thermal hyperesthesia and reduced paw edema in a dose-dependent manner 2 h after the carrageenan injection. The effect of CP-96,345 on thermal hyperesthesia was stereospecific, but that on paw edema was not. Posttreatment with intravenous CP-96,345 and intravenous FK224 failed to reduce the level of thermal hyperesthesia or paw edema, and intrathecal injections, either pre- or posttreatment, had no effect on thermal hyperesthesia or paw edema. These data indicate that: 1) spinal NK1 and NK2 receptors do not play an important role in development and maintenance of thermal hyperesthesia evoked by paw carrageenan, and 2) the peripheral NK1 receptor may play an important role in the development of thermal hyperesthesia, but not of paw edema.

Contribution of NK 1 and NK 2 receptor activation to high threshold afferent fibre evoked ventral root responses in the rat spinal cord in vitro

The contribution of neurokinin and NMDA receptor activation to the generation of the prolonged high threshold evoked ventral root potential (VRP) and its temporal summation has been assessed in the neonatal rat hemisected spinal cord maintained in vitro. High intensity single shock stimulation of the dorsal roots evoked a prolonged VRP ( 9.81 ± 0.9s, n = 11). A low frequency (1–10 Hz) repetitive stimulation (20 s duration) of high threshold afferent fibres evoked a summated VRP. This summated VRP reflected the temporal summation of EPSP's in spinal cord neurones which underlies the phenomenon of ‘Windup’. The integrated area and duration of the high threshold evoked VRP were significantly reduced following superfusion of the spinal cord with the NK2 receptor antagonist MEN, 10376 (100 nM). In the presence of D-AP5 (20 μM) the area of the C-fibre evoked VRP was also significantly reduced. The VRP duration was unaffected. Superfusion with either CP-96,345 (500 nM) or RP,67580 (100 nM), both non-peptide NK1 antagonist, did not have any significant effect upon the area or duration of the prolonged VRP following high threshold stimulation. The simultaneous application of D-AP5 (20 μM) with either MEN,10376 (100 nM) or CP-96,345 (500 nM) together produced a reduction in the area of the evoked VRP which was comparable to the value obtained by addition of their individual effects. The amplitude of the summated VRP was significantly reduced following application of D-AP5 (20 μM). No significant effect upon the amplitude was observed following separate application of either MEN,10376 (100 nM), CP-96,345 (500 nM) or RP,67580 (100 nM). The effect upon the amplitude of the summated VRP, of the simultaneous application of D-AP5 and MEN,10376, was not significantly different from the effect of D-AP5 alone. In contrast, the effect of the simultaneous application of D-AP5 and CP-96,345 was significantly different from the effect of D-AP5 alone. These data suggest that the long duration synaptic events evoked following brief activation of high threshold dorsal root afferent fibres mainly involves the activation of the NK2 tachykinin and NMDA receptor subtypes. More sustained nociceptive input however is associated with the additional activation of the NK1 receptor subtype. This contribution however is only revealed when in co-operation with the action of the NMDA receptor antagonist D-AP5.

Non‐peptide antagonists, CP‐96,345 and RP 67580, distinguish species variants in tachykinin NK1 receptors

1. The potency of the non-peptide antagonists CP-96,345 and RP 67580 on NK1 receptor-stimulated [3H]-inositol phosphate accumulation in cell lines or tissue from three different species has been examined. 2. We have used: UC11 cells, derived from a human astrocytoma, and rat LRM55 glial cells, both of which express large numbers of functional NK1 receptors, and the well characterized guinea-pig ileum which expresses both NK1 and NK3 receptors. 3. RP 67580 has an approximately 25 fold lower affinity for NK1 receptors in human UC11 cells (Kd = 194 nM) than in rat LRM55 cells (Kd = 7.9 nM), in contrast CP-96,345 has an approximately 200 fold lower affinity in rat LRM55 cells (Kd = 210 nM) relative to human UC11 cells (Kd = 0.99 nM). The pharmacological profile of CP-96,345 and RP 67580 in guinea-pig ileum was similar to that observed in human UC11 cells. 4. In conclusion, we have demonstrated that previously reported species differences in binding affinities for the non-peptide NK1 antagonists, CP-96,345 and RP 67580, are also observed in inhibition of NK1 receptor stimulated hydrolysis of inositol phospholipids.

The trophic effect of beta-amyloid 25-35 peptide is not mediated by NK1 or bombesin receptors.

beta-Amyloid peptide and spantide have previously been described to have trophic effects on hippocampal neurones in vitro. We report here that bombesin and [Pro9]-substance P also show a neurotrophic effect on cultured hippocampal neurones. The neurotrophic effect of spantide or a beta-amyloid fragment containing amino acids 25 to 35 was not blocked by addition of the NK1 receptor agonist, substance P or the nonpeptide NK1 antagonist, RP 67580. For the bombesin-related peptides, the antagonist [Tyr4-DPhe12]-bombesin also provokes a trophic response, but the agonist alytesin and the antagonist [Leu13-psi-(CH2NH) Leu14]-bombesin have no effect on neurite growth. These results suggest that the observed trophic responses are unlikely to be mediated by a classical NK1 or bombesin receptor.

Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors.

Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer. Phosphoramidon, 10(-5) M, was added to the bath to inhibit neurokinin metabolism. SR 48968 induced a parallel shift to the right of the concentration-response (C/R) curves to [Nle10]-NKA(4-10), a specific NK2 receptor agonist. The antagonism was of the competitive type, with a pA2 of 9.40 +/- 0.19 (slope = 0.95 +/- 0.08, n = 13). The (R)-enantiomer of SR 48968 was 100-fold less potent and a noncompetitive antagonist (slope = 0.56 +/- 0.11, n = 8); pA2 and slope of the racemate were 8.86 +/- 0.21 and 1.09 +/- 0.21 (n = 7), respectively. Under similar conditions, racemic CP-96,345, a nonpeptide NK1 antagonist, did not modify the C/R curves to [Nle10]-NKA(4-10) until 10(-7) M. SR 48968 did not modify C/R curves to acetylcholine, histamine, KCI, or PGF2 alpha on the human isolated bronchus. Finally, SR 48968 shifted to the right C/R curves to substance P on isolated human bronchi, whereas racemic CP-96,345 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of NK-1 receptors in guinea pig and rat brain membranes with NK-1 peptides and a non-peptide antagonist

The major finding of the present investigation is the demonstration of different NK-1 receptors in rat and guinea pig brain membranes with CP 96345 (non-peptide NK-1 antagonist) and R-544 (NK-1 peptide antagonist). We used [ 3H]Sar 9, Me(O 2) 11]SP, the highly selective ligand for NK-1 receptor to compare NK-1 binding sites in rat and guinea pig brain membranes. Scarchard analysis revealed the existence of a single population of [ 3H][Sar 9, Met(O 2) 11]SP binding sites in both preparations. The affinity and the maximal number of bindind sites were found closely similar in rat ( K d 2 nM, B max = 37 fmol/mg protein) and guinea pig brain membranes ( K d = 3 nM, B max = 25 fmol/mg of protein). The order of potency of neurokinins to inhibit [ 3H][Sar 9, Met(O 2) 11]SP binding from rat brain (SP > NKA > NKB) was found different of that observed on guinea pig brain (SP > NKB > NKA). Results obtained with [Sar 9, Met(O 2) 11]SP, [βAla 8]NKA(4–10) and [MePhe 7]NKB suggest that selective agonists cannot discriminate between NK-1 receptors of different species. Using the non-peptide antagonist CP 96345 and the tripeptide R-544, we found that these two NK-1 antagonists discriminate between rat and guinea pig [ 3H][Sar 9, Met(O 2) 11]SP binding sites.

Modulation of the rat mesolimbic dopamine pathway by neurokinins

The locomotor activity (LMA) response induced after infusion of selective neurokinin (NK) agonists into the cell body (A10) and a terminal region of the mesolimbic pathway of the rat was investigated. Infusion of the NK1 receptor-selective agonist, GR73632, into the ventral tegmental area (VTA: A10) or the nucleus accumbens (NAS) significantly and dose-dependently increased basal LMA. Agonists selective for the NK2 and NK3 receptors, GR64349 and senktide respectively, had no effect on LMA after intra-NAS infusion. The LMA induced by GR73632 is mediated via dopamine (DA) since the response was abolished by haloperidol. From these studies it would appear that the elevated LMA reported previously after VTA or NAS administration of substance P probably occurs via NK1 receptors. Such data supports the notion that endogenous NKs are likely to be important in modulating the mesolimbic DA pathway and, as a consequence, compounds which antagonise their effects could be useful for the treatment of disorders associated with this system. However, simultaneous infusion of the NK1 agonists, +/- CP-96,345 and its analogue CPQ, into the VTA did not attenuate the LMA induced after intra-VTA infusion of GR73632. Co-infusion of the NK1 antagonist CPQ, but not +/- CP-96,345, attenuated the LMA response induced by GR73632 in the NAS. The apparent poor susceptibility of these responses to blockade by the recently developed non-peptide NK1 antagonists was unexpected but may reflect their poor affinity for the rat variant of the NK1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

The substance P (NK1) receptor antagonist (+/-)-CP-96,345 causes sedation and motor impairment in Swiss albino mice in the black-and-white box behavioral paradigm.

In order to test the suggested involvement of substance P (NK1) receptors in anxiety, the non-peptide NK1 antagonist (+/-)-CP-96,345 was tested in Swiss albino mice using the black-and-white box behavioral paradigm. Intraperitoneal (+/-)-CP-96,345 dose-dependently decreased the motor activity and the number of exploratory rearings in both the brightly lit and dark compartment as well as the transitions between the compartments, whereas it increased the latency of the initial movement into the dark compartment as well as the time spent in the light section. ED50 or ID50 values ranged from 1.9 to 3.6 mg/kg and Hill slopes from 1.4 to 5.0. (+/-)-CP-96,345 also produced rotatory behavior of no preferred lateralization as well as the Straub phenomenon in some animals. The effects of (+/-)-CP-96,345 (5 mg/kg) were not affected by 2 mg/kg naloxone (i.p.) which was also ineffective when given alone. Thus, (+/-)-CP-96,345 does not display any anxiogenic effect but causes dose-dependent sedation and motor impairment.