PubMed · 9263607
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C Gennari. 1997. Ipriflavone: background.. https://pubmed.ncbi.nlm.nih.gov/9263607/
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A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f (2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benz yl- N-methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (Ki = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.
1. The effects of an opioid (D-Ser-Leu-enkephalin-Thr; DSLET) were tested on synaptic actions of non-nociceptive afferents: group I and II muscle afferents and low-threshold skin afferents. They were tested on population EPSPs (field potentials) evoked in the dorsal horn and the intermediate zone of mid-lumbar segments, and on monosynaptically evoked responses of single interneurones at the same location. DSLET was applied locally (ionophoretically) at locations at which the field potentials were maximal and close to the selected neurones. 2. DSLET potently depressed transmission from group II muscle afferents and from low-threshold skin afferents. Transmission to neurones located in the dorsal horn or in the intermediate zone was depressed to a similar extent. The depression was readily antagonized by naloxone. Transmission from group Ia or Ib muscle afferents to neurones located in the intermediate zone was not affected, or was facilitated by DSLET. 3. The results show that DSLET has similar depressive actions on spinal neurones to monoamines, but its actions are more widespread. Like monoamines it affects transmission from nociceptors and group II muscle afferents, but in addition it gates transmission from low-threshold cutaneous afferents. Furthermore its effects do not appear to be restricted to interneurones at particular locations since it depressed responses of dorsal horn interneurones (gated by serotonin) as well as intermediate zone interneurones (gated by noradrenaline).
The mRNA for leukemia inhibitory factor (LIF), a neuroimmune signaling molecule, is elevated during skin inflammation produced by intraplantar injection of complete Freund's adjuvant (CFA). Moreover, although LIF knock-out mice display normal sensitivity to cutaneous mechanical and thermal stimulation compared with wild-type mice, the degree of CFA-induced inflammation in mice lacking LIF is enhanced in spatial extent, amplitude, cellular infiltrate, and interleukin (IL)-1beta and nerve growth factor (NGF) expression. Conversely, local injection of low doses of recombinant LIF diminishes mechanical and thermal hypersensitivity as well as the IL-1beta and NGF expression induced by CFA. These data show that upregulation of LIF during peripheral inflammation serves a key, early anti-inflammatory role and that exogenous LIF can reduce inflammatory hyperalgesia.