Influence of L-naphthylalanine in position 3 of AVP and its analogues on their pharmacological properties.
We describe the synthesis and pharmacological properties of two series of analogues: one which consists of three peptides having L-1-naphthylalanine in position 3 and the second composed of analogues substituted in position 3 with L-2-naphthylalanine. All peptides were tested in bioassays for pressor and antidiuretic activities. We also checked the uterotonic activity in vitro. We observed that the activity of counterparts in both series is, in two cases, strikingly different. One of the new analogues, [(L-2-Nal)3,(D-Arg)8]VP is among the most potent antagonists of the vasopressor response to AVP. Moreover, it is the first potent V1 antagonist devoid of antiuterotonic activity. This analogue was designed without modification of position 1, which was previously thought to be essential for substantial pressor antagonism. Two other peptides, [Mpa1;(L-2-Nal)3;(D-Arg)8]VP and [Mpa1,(L-1-Nal)3,D-Arg)8]VP, are highly potent V2 agonists. The second analogue is highly selective. With the exception of [(L-2-Nal)3]AVP, which showed weak antioxytocic activity, (L-Nal)3 modification resulted in the almost complete removal of interaction of our analogues with oxytocic receptors in vitro. Our results suggest that position 3 in AVP and its analogues is important not only for binding and recognition as previously though, but also for pressor, antidiuretic and uterotonic activities. We also assume that the hindering effect caused by bulky naphthyl moiety has a significant impact on the bioactive conformations of molecules which contain Nal residue, and can thus influence their interaction with V1, V2 and oxytocic receptors.
Lammek
B
B
Department of Chemistry, University of Gdañsk, Poland. bernard@hebe.chem.univ.gda.pl
Czaja
M
M
Derdowska
I
I
Rekowski
P
P
Trzeciak
H I
HI
Sikora
P
P
Szkróbka
W
W
Stojko
R
R
Kupryszewski
G
G
D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis / Q000494:pharmacology
D004232:Diuretics; D009842:Oligopeptides; D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; C103278:arginine vasopressin, 2-naphthylalanine(3)-; D001127:Arginine Vasopressin