1. Inhibition of neurogenic vasodilation and plasma extravasation by substance P antagonists, somatostatin and [D-Met2, Pro5]enkephalinamide
F Lembeck, J Donnerer, L Barthó Eur J Pharmacol. 1982 Nov 19;85(2):171-6. doi: 10.1016/0014-2999(82)90462-9.
The substance P (SP) analogues [D-Pro2, D-Phe7, D-Trp9]SP and [D-Pro2, D-Trp7,9]SP, which have been reported to be SP antagonists, inhibited the vasodilation and plasma extravasation induced by antidromic stimulation of the saphenous nerve or by i.a. infusion of SP. Somatostatin inhibited the vasodilatation and plasma extravasation induced by saphenous nerve stimulation, but had no effect on the vascular responses to i.a. infused SP. The opiate agonist [D-Met2, Pro5]enkephalinamide inhibited the vasodilation evoked by antidromic nerve stimulation in a naloxone reversible manner, but did not change the effect of i.a. infusion of SP. Calcitonin and caerulein had no effect on neurogenic vasodilatation. These results further support the concepts that neurogenic vasodilatation and plasma extravasation are mediated by SP, and that somatostatin and opiates inhibit the release of SP from peripheral sensory nerve endings.
2. Structure-activity relationships of eighteen somatostatin analogues on gastric secretion
M P Brown, D H Coy, A Gomez-Pan, B H Hirst, M Hunter, C Meyers, J D Reed, A V Schally, B Shaw J Physiol. 1978 Apr;277:1-14. doi: 10.1113/jphysiol.1978.sp012256.
1. The effect of somatostatin and eighteen somatostatin analogues on pentagastrin-stimulated gastric acid and pepsin secretion was investigated in the conscious vagotomized cat prepared with chronic gastric fistulae. The majority of the analogues are peptides where D-amino acids are incorporated into the molecule instead of the natural L-isomers. 2. The ID50 for cyclic-somatostatin inhibition of near-maximal gastric acid secretion stimulated by pentagastrin 8 microgram kg-1 hr-1 was found to be 1.29 +/- 0.13 n-mole kg-1 hr-1. Pentagastrin-stimulated pepsin secretion had a lower threshold to somatostatin inhibition than did acid secretion. 3. D-Phe6, D-Phe7, D-Thr10, D-Thr12 and D-Phe6-D-Trp8 analogues all show low biological activity against the secretion of gastric acid and pepsin, growth hormone, insulin and glucagon. None of these analogues are antagonists of the cyclic-somatostatin inhibition of gastric secretion, suggesting that they have low affinity for this somatostatin receptor. 4. The analogues under investigation show parallel changes in activity against gastric and growth hormone secretion, suggesting a similarity between the gastric and growth hormone receptors for somatostatin. 5. D-Cys14 analogues are equipotent with or have a greater potency than cyclic-simatostatin in inhibiting the secretion of gastric acid, growth hormone and glucagon but show low insulin inhibiting activity.
3. Substance P analogues containing D-histidine antagonize the behavioural effects of intrathecally co-administered substance P in mice
T Sakurada, T Yamada, S Sakurada, K Kisara, M Ohba Eur J Pharmacol. 1989 Dec 19;174(2-3):153-60. doi: 10.1016/0014-2999(89)90307-5.
The antagonistic effect of newly synthesized substance P (SP) analogues containing D-histidine was examined on behavioural responses induced in mice by SP, neurokinin (NK) A, physalaemin, eledoisin, somatostatin and bombesin. [D-Pro2,D-Trp7,9]SP (DPDT-SP) and [D-Arg1,D-Trp7,9,Leu11]SP (spantide) were used as references for comparison. When co-administered with SP intrathecally, all the SP analogues used decreased the SP-induced response which consists of scratching, biting and licking. DPDT-SP and spantide attenuated non-specifically the SP-like behavioural responses induced by physalaemin, eledoisin, NK A and somatostatin. In general, the introduction of D-histidine in position 9 of the SP molecule resulted in potent antagonistic activity of the SP derivative on the behavioural responses to SP. Of these SP analogues, [D-Arg1,D-Pro2,4,D-Phe7,D-His9]SP attenuated selectively the behavioural responses produced by NK-1 receptor agonists such as SP and physalaemin. Simultaneous injection of [D-Phe7,D-His9]SP-(6-11) selectively inhibited the SP-induced behavioural response without affecting the other peptide-induced behavioral response. The results suggest that the behavioural antagonism induced by [D-Arg1,D-Pro2,4,D-Phe7,D-His9]SP and [D-Phe7,D-His9]SP-(6-11) is probably due to the specific blockade of spinal NK-1 receptors.
