Disease relevance of LY303870

• Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth [1].
• Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw [1].
• Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870 [2].
• Previously we observed that the substance P receptor (NK(1)) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II [2].
• 2 The initial hypotension (-18+/-2.0 mmHg at 1 min) and the tachycardia (110+/-10 b.p.m.) produced by the intrathecal (i.t.) injection of the stable NK(1) receptor agonist [Sar(9), Met(O(2))(11)]-SP (Sar9, 0.65 nmol) at T-9 spinal cord level was inhibited by the prior injection of 65 nmol LY306740 or LY303870 (NK(1) receptor antagonists) [3].

High impact information on LY303870

• On the other hand, the paclitaxel-induced pulmonary vascular hyperpermeability was reversed by sensory denervation with capsaicin or pretreatment with LY303870 and SR48968, NK1 and NK2 antagonists, respectively [4].
• Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870 [2].
• SP and SP(6-11) responses were blocked by NK-1 antagonists SR140333 and LY303870 [5].
• Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action [6].
• Unlabeled LY303870 potently inhibited the binding with an IC50 of 0.56 nM, whereas the less active (S)-enantiomer (LY306155) was substantially less potent [7].

Chemical compound and disease context of LY303870

• In addition, LY303241, LY303870 and LY306740 neither affected the hypotension and the salivation induced by carbachol nor the increases in mean arterial pressure and heart rate induced by the tachykinin NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10) [8].

Biological context of LY303870

• 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 [7].
• 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 [9].
• LY303870 and LY306740 were devoid of direct effects while LY303241 decreased blood pressure and heart rate for 1 and 10 min, respectively [8].

Anatomical context of LY303870

• The nonpeptide NK-1 receptor antagonists LY303870 and LY306740 block the responses of spinal dorsal horn neurons to substance P and to peripheral noxious stimuli [10].
• LY303870 selectively inhibited the late component of the response to electrical stimulation of the superficial peroneal nerve [10].
• Saturable transport of the neurokinin-1 non-peptide antagonist LY303870 across the rat blood-brain barrier after intravenous administration [11].
• LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs [12].

Associations of LY303870 with other chemical compounds

• Capsaicin desensitization and the tachykinin NK(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, partially inhibited the leakage [13].

Gene context of LY303870

• 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 [9].
• LY303870 and LY306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor [8].

References