Further evidence for the existence of NK2 tachykinin receptor subtypes.
1. We have evaluated the biological activity of a number of neurokinin A (4-10), (NKA (4-10)) analogues in the endothelium-deprived rabbit isolated pulmonary artery (RPA) and hamster isolated trachea (HT), two tissues rich in different NK2 receptor subtypes. 2. MDL 28,564, a pseudopeptide selective for NK2 receptor sites, behaved as a full agonist in the RPA, while in the HT it competitively antagonized NKA or [beta Ala8]-NKA (4-10) contractile effects. 3. The peculiar behaviour of MDL 28,564 in the RPA and HT may be explained neither by a difference in receptor reserve between the two organs (the reserve being three times greater in RPA than in the HT) nor by a different affinity for the two receptor subtypes (identical dissociation constants, pKA or pKB, calculated in the RPA and in the HT). On the other hand, MDL 28,564 displayed a very different intrinsic efficacy for the two receptor subtypes. 4. The novel peptides MEN 10,295 ([Trp7, beta Ala8]-NKA-(4-10)) and MEN 10,296 ([Tyr5, Trp7, beta Ala8]-NKA-(4-10] behaved as weaker agonists than MDL 28,564 in the RPA, but retained appreciable agonist activity also in the HT. 5. The novel peptides: MEN 10,282 ([Tyr5, D-Trp6,8, Trp9, Arg10]-NKA-(4-10], MEN 10,449 ([diI-Try5, D-Trp6,8,9, Arg10]-NKA-(4-10] and the cyclic hexapeptide L 659,877 (cyclo [Leu-Met-Gln-Trp-Phe-Gly]) behaved as competitive antagonists against NKA contractile effects both in the RPA and HT. MEN 10,282 and MEN 10,449 were unable to distinguish between the NK2 receptor subtypes, having almost the same affinity in the two organs. On the other hand L 659,877 was about 15 times more potent in the HT than in the RPA. 6. These results provide further evidence for NK2 receptors heterogeneity and are useful in outlining pharmacological features of the two subtypes present in the RPA and HT.
Patacchini
R
R
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Astolfi
M
M
Quartara
L
L
Rovero
P
P
Giachetti
A
A
Maggi
C A
CA
D000595:Amino Acid Sequence; D000818:Animals; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D018039:Receptors, Tachykinin; D015320:Tachykinins / Q000037:antagonists & inhibitors; D014132:Trachea / Q000187:drug effects
D010446:Peptide Fragments; D010455:Peptides; D010456:Peptides, Cyclic; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; C068459:L 659874; C066015:MDL 28564; D015288:Neurokinin A