Disease relevance of RP-67580

• Thus we conclude that RP 67580, a SP antagonist, belongs to a class of drugs that may be useful in the management of various clinical pathologies where pain and neurogenic inflammation are involved [1].
• Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP(8-37) and RP67580, respectively, abolished the SLIGRL-NH(2)-induced stimulatory effect on transit in ischemia/reperfusion [2].
• This was confirmed by finding no reversal of NGF-induced hyperalgesia by RP67580, another NK1 receptor blocker [3].
• RP67580 pre-treatment at 0.1 mg/kg i.p. had no effect, but at both I and 10 mg/kg, attenuated progressive tactile hypersensitivity without changing baseline values [4].
• CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) [5].

Psychiatry related information on RP-67580

• In contrast, RP 67580 decreased exploratory behavior only in the white section, whereas crossings and rearings in the black section were not changed [6].

High impact information on RP-67580

• Furthermore, pretreatment with either CP, 96-345, or RP-67580 two selective NK-1 receptor antagonists inhibited poly-L-lysine-induced airway hyperresponsiveness and plasma protein extravasation [7].
• Contractions induced by SP and septide (a selective NK1 agonist) in guinea pig ileum were competitively inhibited by RP 67580 (pA2 = 7.16 and 7.59, respectively) [1].
• Because these studies suggested that CGRP potentiated the afferent renal nerve activity responses to substance P, we examined whether the afferent renal nerve activity response to CGRP was blocked by a substance P receptor antagonist, RP67580 [8].
• RP67580 blocked the afferent renal nerve activity response to CGRP by 85+/-12% (P<0.02) [8].
• The NK-1 antagonist RP 67580 also showed a higher potency for [3H]ALIE-124 than for [3H][Pro9]SP-specific binding sites [9].

Chemical compound and disease context of RP-67580

• Pretreatment with RP 67580 but not MEN 10376 prevented this, but when RP 67580 was administered 25 min after the application of mustard oil, the established hypersensitivity of the flexor motor reflex was not reversed [10].
• Morphine and L-baclofen partially reversed established STZ-induced mechanical hyperalgesia, whilst the NK-1 receptor-antagonist RP-67580, the NMDA-antagonists MK801 and ketamine, and the nitric oxide synthase inhibitor L-NAME were without significant effect [11].
• 3. Capsaicin-induced hyperalgesia was prevented and reversed by the NK1 receptor antagonists CP 99994 (100 nmol) and RP 67580 (1 nmol) [12].
• SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of thermal hyperalgesia and prostaglandin E2 release, but not release of amino acids) [13].
• We have used one peptide (FK888) and two non-peptide ((+/-)-CP-96,345 and RP 67580) antagonists, along with the preferred endogenous agonist, substance P, to compare the pharmacological (binding) profile of NK1 receptors expressed by human B lymphoblastoma (IM9) and astrocytoma (U373 MG) cells [14].

Biological context of RP-67580

• In comparison, the affinity of RP67580, the least selective molecule, was most affected by changes at position 116, and combination with mutations at either position 97 (V-->E) or position 290 led to the human receptor phenotype [15].
• 3. Dural vasodilatation to trigeminal stimulation was not inhibited by the calcitonin gene-related peptide-1 receptor (CGRP-1) antagonist hCGRP8-37 (15 or 50 microg kg(-1) i.v), or the neurokinin-1 receptor antagonist RP 67580 (0.1 mg kg(-1) i.v.) although both antagonists inhibited the nasal response [16].
• Racemic RP67580 inhibited calcium entry into depolarized strips of guinea-pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 +/- 115 nM), inhibited [3H]-diltiazem binding to rabbit skeletal membranes (IC50 = 298 nM) and depressed high threshold calcium currents in neurones cultured from rat cortex (10% inhibition at 10 microM) [17].
• 4. RP67580 (10-9 mol mouse-1 i.v.) reduced the increased tracheal vascular permeability induced by a second exposure to DNS in DNFB-sensitized mice completely when injected 15 min before the second challenge (P<0.001, ANOVA) [18].
• Antagonists to the NK1 and NK2 neurokinin receptor subtypes, RP 67580 and L-659877, respectively, were without effect, whereas the antagonist to the CGRP1 receptor, CGRP8-37, prevented the loss of vasoconstriction during repetitive nerve stimulation [19].

Anatomical context of RP-67580

• Moreover, RP 67580 displayed the profile of a specific antagonist of NK1 receptors: it was not active on NK2 and NK3 receptors as seen in binding assays and in isolated preparations of rabbit pulmonary artery and rat portal vein [1].
• The selective NK1 antagonist (RP 67580; 5.10(-9) mol/mouse), administered 5 min before and 1 h after the challenge, suppressed mucosal exudation and leukocyte accumulation in the airways 24 h after the challenge [20].
• RP 67580 was a competitive inhibitor of SP responses, with an inhibition constant (KB) of 13 +/- 2 nM, in agreement with displacement studies of [3H]SP binding to membranes and intact transfected cells (Ki values of 10 +/- 4 nM, and 1.16 +/- 0.06 nM, respectively) [21].
• 3. RP 67580 (10 nM) did not modify electrically-evoked release of calcitonin gene-related peptide-LI from rat spinal cord slices [22].
• The non-peptide neurokinin1 receptor antagonist, RP 67580, blocks neurogenic plasma extravasation in the dura mater of rats [23].

Associations of RP-67580 with other chemical compounds

• We describe here the pharmacological properties of RP 67580 [(3aR,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] perhydroisoindol-4-one], a nonpeptide antagonist of substance P (SP) [1].
• 4. The acid-evoked hyperaemia in the left gastric artery was left unaltered by atropine and the substance P receptor antagonist RP-67580 [24].
• The pharmacological profile of CP-96,345 and RP 67580 in guinea-pig ileum was similar to that observed in human UC11 cells [25].
• The induction of long-term potentiation by N-methyl-D-aspartate, substance P or neurokinin A was blocked by intravenous application of the receptor antagonists dizocilpine maleate (0.5 mg/kg), RP67580 (2 mg/kg) or SR48968 (0.2 mg/kg), respectively [26].
• Effects of the tachykinin NK1 receptor antagonist, RP 67580, on central cardiovascular and behavioural effects of substance P, neurokinin A and neurokinin B [27].

Gene context of RP-67580

• Blockade of the NK1 receptor with RP67580, but not blockade of the CGRP receptor with CGRP(8-37), caused more severe impairment in postischemic recovery in both TRPV1(-/-) and WT hearts than in untreated hearts in both genotypes [28].
• Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge [29].
• The non-peptide NK1 receptor selective antagonist RP67580 inhibited responses to SPOMe, septide and/Sar9/-SP-sulphone to varying degrees with IC50 values against each of 16.0 nM (10.7-23.4 nM), 19.8 nM (8.9-37 nM) and 58.0 nM (41-89 nM), respectively [30].
• 5. Our results indicate that RP 67580 is a selective and high affinity antagonist at central NK1 tachykinin receptors in the rat [27].
• Neurokinin A produced increases in dural vessel diameter which were unaffected by the NK2 receptor antagonist SR 48968 but were blocked by RP67580, suggesting that neurokinin A can act through NK1 receptors to produce dural vasodilation in rats [31].

Analytical, diagnostic and therapeutic context of RP-67580

• A non-peptide neurokinin1 (NK1) receptor antagonist, RP 67580, that is selective for the rodent subtype of the NK1 receptor, dose-dependently reduced plasma extravasation in the dura mater produced by electrical stimulation of the trigeminal ganglion in rats, with an ID50 of 0.6 micrograms kg-1 [23].
• The SP-induced renal inhibitory effects during the first 30 min were abolished in rats subjected to bilateral renal denervation 1 week earlier or in rats injected i.t. 5 min earlier with 6.5 nmol RP 67580 [32].
• Afferent firing rate was assessed following close intraarterial injection of the NK1 antagonist RP67580 followed by administration of 20 nmol nociceptin [33].
• Neither the basal flow nor the stimulus-evoked flow was significantly changed by topical administration of SP, the SP analog septide, or the NK1 antagonist RP 67580 [34].
• This reflex response was blocked by either neonatal pretreatment with capsaicin (50 mg/kg, s.c.) or intrathecal injection of the substance P receptor antagonist RP 67580 (7.8 nmol, at the spinal level L5-L6), suggesting that it is mediated exclusively by substance P-containing primary afferent fibres [35].

References