1. Antagonists for the neurokinin NK-3 receptor evaluated in selective receptor systems
G Drapeau, N Rouissi, F Nantel, N E Rhaleb, C Tousignant, D Regoli Regul Pept. 1990 Nov 15;31(2):125-35. doi: 10.1016/0167-0115(90)90115-d.
Four isolated vessels that are monoreceptor systems for neurokinins, the dog carotid artery and rabbit jugular vein (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3), were used to compare the activities of selective neurokinin agonists and evaluate the affinities of new NK-3 antagonists. Chemical modifications in the partial sequences NKA (4-10) and NKB (4-10), particularly the replacement of Val7 with an aromatic residue (Tyr, MePhe or Trp) and the extension of the peptide backbone in position 8, obtained with beta-Ala, led to compounds that maintain weak agonistic activities on the NK-1 and NK-2, and some of them also on NK-3 receptors but exert potent antagonism against NKB on the NK-3 receptor of the rat portal vein. Antagonistic affinity is the highest when Trp is used in position 7 of [beta-Ala8]-NKA (4-10) and MePhe in position 7 of [beta-Ala8]-NKB (4-10). Antagonism is selective for NKB or [MePhe7]-NKB, and appears to be specific, since the most active compound [Trp7, beta-Ala8]-NKA (4-10) is inactive against bradykinin on the rabbit jugular vein (B2 receptor), against SP on the rabbit jugular vein (NK-1 receptor), against desArg9-bradykinin on the rabbit aorta (B1 receptor), and against angiotensin II and histamine (AT and H receptors, respectively) in the rabbit aorta. The new NK-3 receptor antagonists described in the present study provide useful tools for neurokinin receptor characterization and for determining the roles of neurokinins in physiopathology.
2. Tachykinins as mediators of slow EPSPs in guinea-pig gall-bladder ganglia: involvement of neurokinin-3 receptors
G M Mawe J Physiol. 1995 Jun 1;485 ( Pt 2)(Pt 2):513-24. doi: 10.1113/jphysiol.1995.sp020747.
1. The effects of endogenous tachykinins and related peptides on intact guinea-pig gall-bladder neurones were investigated with single-electrode voltage- and current-clamp recording techniques. 2. Pressure ejection of substance P (100 microM) caused a long lasting membrane depolarization that was associated with a decrease in input resistance. In cells that were voltage-clamped to their resting membrane potential, substance P activated an inward current. 3. The reversal potentials of the substance P-induced depolarization and inward current were congruent to 0 mV. In a low-Na+ solution, the substance P-induced depolarization and inward current were reduced in amplitude. 4. Substance P increased the excitability of neurones, as evidenced by a greater anodal break activity and an increase in the number of action potentials generated during a depolarizing current pulse. 5. Substance P, neurokinin A (NKA) and neurokinin B (NKB) were applied by superfusion to determine the relative potencies of these tachykinins. NKB was the most potent, with an EC50 of 24 nM. The EC50 values for NKA and substance P were 47.8 and 281 nM, respectively. 6. The neurokinin-3 (NK-3) receptor agonist senktide depolarized neurones with an EC50 of 6.3 nM. Neither the NK-1 receptor agonist [Sar9,Met(O2)11]-substance P nor the NK-2 receptor agonist [beta-Ala8]-NKA(4-10) caused a measurable depolarization. 7. The NK-3 antagonist [Trp7,beta-Ala8]-NKA (4-10) inhibited the responsiveness of gall-bladder neurones to substance P with a KB (dissociation constant of receptor antagonist) of 49 nM, and depressed both capsaicin-induced depolarizations and stimulus-evoked slow EPSPs. 8. These data indicate that tachykinins mediate slow EPSPs in guinea-pig gall-bladder ganglia by activating NK-3 receptors on gall-bladder neurones. It is proposed that in response to inflammation or high intraluminal pressure, tachykinins may be released within ganglia by sensory fibres and act directly on intrinsic neurones to facilitate ganglionic transmission.
3. Neurokinin A and senktide attenuate scopolamine-induced impairment of spontaneous alternation performance in mice
M Ukai, N Shinkai, T Kameyama Nihon Shinkei Seishin Yakurigaku Zasshi. 1996 Jun;16(3):97-101.
The effects of intracerebroventricular injections of the neurokinin-2 (NK-2) receptor agonist neurokinin A and the neurokinin-3 (NK-3) receptor agonist senktide on scopolamine (sc)-induced amnesia were investigated based on spontaneous alternation performance in mice. Spontaneous alternation performance is based on spatial working memory which produces a natural tendency to explore a less recently visited arm in a Y-maze. Neurokinin A (0.1-3 micrograms) or senktide (0.0003-0.03 microgram) alone did not influence either spontaneous alternation performance or total arm entries. However, neurokinin A (0.3 and 1 microgram) and senktide (0.003 and 0.03 microgram) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without affecting the scopolamine (1 mg/kg)-induced increase in total arm entries. Although the effects of neurokinin A (0.3 microgram) on the scopolamine-induced impairment of spontaneous alternation performance were almost completely antagonized by pretreatment with the NK-2 receptor antagonist cyclo (Gln-Trp-Phe-Gly-Leu-Met) (1 microgram), the inhibitory effects of senktide (0.003 microgram) were not influenced by pretreatment with the NK-3 receptor antagonist [Trp7, beta-Ala8]neurokinin A-(4-10). These findings suggest that neurokinin A inhibits the scopolamine-induced impairment of spontaneous alternation performance associated with working memory through the mediation of tachykinin NK-2 receptors, while senktide has some pharmacological action other than its effects on NK-3 receptors.
