Synthetic C5a receptor agonists. Pharmacology, metabolism and in vivo cardiovascular and hematologic effects.
Recent investigations have produced novel compounds that act on the receptor for anaphylatoxin C5a. These products are C-terminal analogues of C5a, some of which are modified extensively. We have measured the receptor affinities of such analogues in a binding assay on human neutrophils (PMNs). We have also characterized their pharmacological profiles in vitro on the isolated rabbit portal vein and pulmonary artery, on superoxide release by PMNs as well as in vivo in the anesthetized rabbit (acute hypotensive and neutropenic effects). The metabolic resistance of these analogues was also evaluated in the presence of different peptidases. One of these compounds, MePhe-Lys-Pro-D-Cha-Phe-D-Arg, behaved as an antagonist on the release of superoxide by neutrophils while exerting agonist activity in all other assays. Its partial agonist status was documented in a receptor down-regulation experiment on PMNs where its activity was compared with those of recombinant C5a and of protamine which behaves as a competitive antagonist on these cells. Degradation studies indicated that the discrepancy between the affinity of certain analogues in vitro and their potency in vivo was probably linked to their metabolic stability.
Drapeau
G
G
Centre de recherche (Université Laval), Hôtel-Dieu de Québec, Canada.
Brochu
S
S
Godin
D
D
Levesque
L
L
Rioux
F
F
Marceau
F
F
D000595:Amino Acid Sequence; D000818:Animals; D001711:Biotransformation; D002319:Cardiovascular System / Q000187:drug effects*; D015936:Complement C5a / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010452:Peptide Biosynthesis; D011479:Protamines / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000187:drug effects*; D013552:Swine
D011479:Protamines; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a