The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.

No abstract

15diimide in 40 ml. of dichloromethane was added dropwise over a 3O-min. period. The resetion mixture was stirred at room temperature for 24 hr., followed by removal of the precipitated N,N'dicyclohexylm by filtration. The filtrate was concentmted by dietillation and the residue was dissolved in benzene, and p d through a column ( 1 ' X 1 0 ' ) of Florisil in benzene. The product, yelloworange crystals, m.p. 37-40', weighed 39 g. (100%) and exhibited a carbonyl absorption at 1790 em.-' in the infrared spectrum of a melted film. A d . Calcd. for CIIH&N: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.85; H, 5.02; N, 7.54. N-(o-Chlozsphenyl)iso"ide. To a slurry of 45 g. (0.2 mole) of N-(o-chlorophenyl)"ic acid in 1 1. of dichlore methane, a solution of 41.2 g. (0.2 mole) of N,N'-dicycl+ hexylearbodiimide in 40 ml. of dichloromethane was added dropwise over a Sin. period. The mixture was stirred at room temperature for 24 hr., followed by filtration of the N,N'-dicyclohexylurea and distillation of the solvent under reduced pressure. The residue in benzene was passed through a column of Florid and the eluates were concentrated to yield 40 g. (97%) of yellow cry&&, m.p. 60-66". Recrystdlization of a sample from 1:1 benzenepetroleum ether @.p. 39-54') gave an analytical sample, m.p 65-67'. A d . Calcd. for CloH&tNCl: C, 57.85; H, 2.91; N, 6.75. Found: C, 58.35; H, 2.73; N, 6.58. The infrared spectrum of a liquid f i l m showed strong carbonyl absorption at 1800 an.-' I 8 -h of N-n-lnbtyliaomaleimide to N-n-hiyl-"ide. A solution of 5.0 g. (0.033 mole) of N-n-butylisomaleimide, 6.06 g. (0.06 mole) of triethylamine, and 3.6 g. (0.06 mole) of acetic acid in 100 ml. of benzene was heated a t reflux for 90 min. The solution was cooled, washed with water, dilute d u m hydroxide solution, and again with water. The bemene was removed under reduced pres-sure and the midue was distilled to yield a clear liquid, b.p. 50-55" (0.5 mm.). Vapor phase chromatographic analysis of this material showed it to be a mixture containing 40% N-n-butylisomaleimide, 59.4% N-n-butylmaleimide and 0.6% of an unknown impurity. The recovery Isomerization of N-phen&aom&imide to N -p h e n y l d eimide. A mixture of 5.0 g. (0.029 mole) of N-phenylisomaleimide, 1.0 g. (0.012 mole) of anhydrous d u m acetate and 15 ml. of acetic anhydride was heated on the steam bath for 1 hr. After the mixture had cooled to 2 5 O , it was poured into 100 ml. of water causing long, yellow needles to separate. These were collected and dried, 4.5 g. (90%) m.p. 90-91'. A mixture melting point with an authentic sample of N-phenylmaleimide was undepressed. When d u m acetate was absent in this reaction, the starting material was recovered.

No abstract

The contributions of B1 and B2 bradykinin receptors to acute and chronic inflammatory hyperalgesia were examined using the peptide B1 receptor antagonist des-Arg9[Leu8]bradykinin and transgenic Bk2r-/- mice. In normal rats and mice, des-Arg9[Leu8]bradykinin (30 nmol/kg i.v. or s.c.) inhibited carrageenan-induced hyperalgesia and the late phase nociceptive response to formalin. The active dose range was narrow, suggesting partial agonist activity of this peptide. In rats with monoarthritis, des-Arg9[Leu8]bradykinin (up to 30 nmol/kg i.v.) failed to reduce the number of vocalisations elicited by gentle flexion and extension of the inflamed limb; however, hyperalgesia was exacerbated by administration of the B1 receptor agonist des-[Arg9]bradykinin (100 nmol/kg i.v.), consistent with other evidence for local induction of B1 receptors during adjuvant-induced arthritis. The nociceptive response to intraplantar injection of bradykinin (10 nmol) and hyperalgesia induced by carrageenan (0.6 mg) were absent in Bk2r-/- mice, indicating that stimulation of B2 receptors is an essential step in the initiation of some nociceptive and inflammatory reactions. However, the nociceptive response to formalin (2.5% intraplantar), including inhibition of the late phase by des-Arg9[Leu8]bradykinin (0.3 nmol), and induction of thermal hyperalgesia by Freund's adjuvant (0.1%) appeared intact in Bk2r-/- mice. These findings support other evidence for an involvement of B1 receptors in inflammatory hyperalgesia and suggest that B1 receptor antagonists may be clinically useful as anti-inflammatory and analgesic drugs.

1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.

Future studies should be conducted using rigorous methodology and validated instruments to measure evidence-based outcomes and should target a wider range of AHCPs. Recommendations are provided on education content and delivery, study methodology and outcome measurement based on insights gained from selected studies.