Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.

The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.

N-terminal truncations of substance P 1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats.

Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the biodistribution and stability of the peptides. Most of the examined compounds alleviated mechanical allodynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by any of the compounds tested. Most of the amino acids in the heptapeptide structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapeptide and its N-terminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.

Enhanced levels of immunoreactive ß-casomorphin-8 in milk of breastfeeding women with mastitis.

An incorrect, superficial suckling technique in breastfeeding frequently leads to milk congestion and sometimes mastitis. In the present study we have examined whether milk congestion may affect levels of the atypical opioid ß-casomorphin-8 in milk and in plasma. We also investigated whether the rate of acute psychosis during the first half year after parturition has declined in Sweden over the years. Milk and plasma samples were collected for peptide analysis from 14 women with mastitis and 10 controls. We found that in a group of 14 late cases of mastitis (median 48 days post partum) the detected mean level of ß-casomorphin-8 in milk was significantly higher and somewhat higher in plasma at the acute stage compared with 2-3 weeks later, after recovery when the symptoms had disappeared, as well as compared to the control subjects. Swedish official statistics show that the incidence of acute psychosis in the first month and in the first half year after birth has declined by a half during the last 30 years. A relationship between postpartum psychosis and elevated ß-casomorphin-8 levels in CSF has been suggested from earlier studies. In this study, milk congestion led to enhanced levels of ß-casomorphin-8 in milk, which may be related to postpartum psychosis and probably also to 'the postnatal blues'.