Disease relevance of CP 99994

• The substance P receptor antagonist CP-99,994 reduces acute postoperative pain [1].
• A 4 hourly administration of CP 99,994 for 20 h during delayed emesis completely abolished the retching and vomiting [2].
• The reductions in the duration of catalepsy and decreases in striatal ACh release associated with CP-99,994 perfusion were positively correlated [3].
• Administration of CP-99,994 (0.75-1.5 mg/kg i.v.), a specific NK1 antagonist, attenuated significantly the evoked reflex bradycardia and depressor response following cardiac receptor (n = 6), but not pulmonary chemoreflex stimulation in vivo [4].
• 2. The NK1 receptor antagonists CP 99994 (10-100 nmol) and RP 67580 (0.1-1 nmol) blocked the development of, and also reversed, SP-induced hyperalgesia [5].

Psychiatry related information on CP 99994

• Subcutaneously administered CP-99,994 antagonized locomotor activity in guinea pigs induced by intraventricular infusion of [Sar9,Met(O2)11]-substance P (50 micrograms) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system [6].
• Effect of intrathecal pretreatment with the neurokinin receptor antagonist CP-99994 on the expression of naloxone-precipitated morphine withdrawal symptoms [7].

High impact information on CP 99994

• In initial experiments, this second phase was attenuated by 1-10 mg of the NK-1 receptor antagonist CP-99,994, given subcutaneously 10, 30, or 60 min before formalin (n = 8-10) and by 20 microgram given intrathecally 20 min after formalin (n = 13); the inactive isomer CP-100,263 was ineffective [8].
• Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994 [9].
• Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough) [10].
• The NTS microinjection of a NK1 antagonist (CP-99,994) in vivo attenuated the tachycardic response to hindlimb pinch [11].
• 5. The potentiating action of ANGII on the chemoreceptor reflex cardiac response was abolished by a neurokinin type 1 (NK1) receptor blocker (CP-99,994, 5 microM) but this had no effect on the baroreceptor reflex [12].

Chemical compound and disease context of CP 99994

• 4. With a cisplatin (5 mg kg-1) emetogenic challenge, administration of CP 99,994 (10 mg kg-1) at 8 hourly intervals, the first injection being administered 30 s post cisplatin, was associated with 4 or more abolitions of emesis during both the acute and delayed phase [2].
• The less active enantiomer of CP-99,994, CP-100,263 (10 mg/kg), did not alter raclopride-induced catalepsy [3].
• Enantiospecific inhibition of emesis induced by nicotine in the house musk shrew (Suncus murinus) by the neurokinin1 (NK1) receptor antagonist CP-99,994 [13].
• Ondansetron was inactive to modify behavior, but CP-99,994 reduced spontaneous locomotor activity and lip licking by 48% (P<0.01) and 79% (P<0.01), respectively; CP-99,994 also abolished spontaneous burrowing activity (P<0.05) [14].
• The emesis was antagonized significantly (P<0.05) by ondansetron (0.3 and 1 mg/kg, i.p.) and (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenlypiperidine hydrochloride (CP-99,994; 10 mg/kg, i.p.), but neither compound reduced defecations and/or tenesmus, with ondansetron (0.3 mg/kg) actually producing a slight increase (P<0.05) [15].

Biological context of CP 99994

• We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects [10].
• The NK(3) receptor endocytosis was blocked by SR-142801 but not by CP-99994 [16].
• 2. CP-99994 displaced [3H]-substance P from cat cortex with IC50 of 0.52 +/- 0.08 nM [17].
• In addition, ODQ (1 microM) increased the electrically-evoked tachykininergic and cholinergic muscle contractions as measured in the presence of scopolamine (100 nM) or of the neurokinin-1 receptor antagonist CP 99994 (100 nM), respectively [18].
• A new NK1 receptor antagonist (CP-99,994) prevents the increase in tracheal vascular permeability produced by hypertonic saline [19].

Anatomical context of CP 99994

• METHODS: The analgesic efficacy of CP-99,994, a NK1 receptor antagonist, was compared with ibuprofen and placebo in 78 subjects undergoing third molar extraction [1].
• Differences in the effects of NK1-receptor antagonists, (+/-)-CP 96,345 and CP 99,994, on agonist-induced responses in guinea-pig trachea [20].
• Antagonism of nociceptive responses of cat spinal dorsal horn neurons in vivo by the NK-1 receptor antagonists CP-96,345 and CP-99,994, but not by CP-96,344 [21].
• In five whole cell recordings of NTS neurons, both the evoked depolarization following cardiac receptor stimulation, and the peak amplitude and duration of vagus nerve-evoked EPSPs were reduced by CP-99,994; synaptic inputs from both peripheral chemoreceptors or pulmonary C-fibres were unaffected [4].
• They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded [22].

Associations of CP 99994 with other chemical compounds

• This effect was reduced by two different NK1 receptor antagonists, CP-99,994 and SR 140333 [23].
• This baroreceptor reflex depression was mimicked by NTS microinjection of substance P and antagonized by microinjection of either bicuculline (a GABAA receptor antagonist) or a neurokinin type 1 (NK1) receptor antagonist (CP-99994) [24].
• 4. Under conditions where the guinea-pig lung parenchymal NK1 receptor was fully occupied by a saturating concentration of either [Sar9Met(O2)11]substance P (1 microM) or CP-99,994 (2.7 microM), residual [125I]-neurokinin A specific binding was inhibited in a concentration-dependent manner by both [beta Ala8]neurokinin A and SR48968 [25].
• 1. The anti-emetic effects of the NK1 tachykinin receptor antagonist, CP 99,994 (10 mg kg-1) were investigated in the ferret using a cisplatin-induced acute (day 1) and delayed (day 2 and 3) retching and vomiting model [2].
• 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 [26].

Gene context of CP 99994

• In comparison, administration of an NK1 antagonist, CP-99,994 (1.5 mg/kg i.v.) to wild-type animals, had no significant effect on baroreceptor reflex performance [27].
• RP 67580 (pA2 8.41) is more active than CP 99994 (pA2 6.06) on the mouse NK1 receptor [28].
• VO2 stimulation was significantly inhibited (P <.05) by the selective NK1 receptor antagonist CP-99994 (1 microM) and the NK2 receptor antagonist SR 48968 (1 microM) (by 42% and 51%, respectively), but PP was not altered [29].
• Antinociceptive activity of the tachykinin NK1 receptor antagonist, CP-99,994, in conscious gerbils [30].
• MATERIALS AND METHODS: We evaluated the activity of the nonpeptide NK-receptor selective antagonists SR 48968 (NK2), SB 223412 (NK3) and CP 99994 (NK1) against neurokinin A (NKA)-induced contractions in isolated dog urinary bladder strips to determine the NK-receptor type which mediates contractile responses to NKA [31].

Analytical, diagnostic and therapeutic context of CP 99994

• CP-99,994 produced analgesia that was significant at 90 minutes (P < 0.01 compared with placebo), but not at subsequent time points [1].
• Both systemic administration and intrastriatal perfusion of CP-99,994 alone decreased striatal ACh release [3].
• 2. A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation [32].
• 4. CP-99,994 (1 mg kg-1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves [22].
• From extracellular recordings of cardioreceptive NTS neurons, CP-99,994 reduced reversibly the total number of evoked spikes, peak firing frequency and response duration evoked by intraventricular injections of veratridine (n = 5) or bradykinin (n = 5) [4].

References