Biological activities of kinins modified at the N- or at the C-terminal end

1979 ◽  
Vol 57 (9) ◽  
pp. 1018-1023 ◽  
Author(s):  
J.-N. Drouin ◽  
P. Gaudreau ◽  
S. St-Pierre ◽  
D. Regoli
Keyword(s):  
Biological Activities ◽  
Rabbit Aorta ◽  
Intrinsic Activity ◽  
Duration Of Action ◽  
Long Acting ◽  
Time Required

A series of analogues of des-Arg9-bradykinin, modified at the N- or C-terminal end, were tested on rabbit aorta strips (receptor B1) and on cat ileum strips (receptor B2) in an attempt to find long-acting agonists and antagonists. It was found that the methylation or the amidation of the C-terminal carboxyl reduces the affinity and (only the amidation) the intrinsic activity of the agonists, while not changing significantly the duration of action of both agonists and antagonists.The addition of a Lys at the N terminal is accompanied by a marked increase of affinity, no changes of intrinsic activity, and a prolongation of the duration of action of agonists. Antagonists behave in a similar way as the agonists and show increased affinity; the time required for inducing full inhibition as well as the duration of action are significantly increased.The pharmacological and physiopathological implications of these results are discussed.

Role of the C-terminal Group for the Biological Activities of Angiotensin

1975 ◽  
Vol 53 (3) ◽  
pp. 383-391 ◽  
Author(s):  
F. Rioux ◽  
W. K. Park ◽  
D. Regoli
Keyword(s):  
Biological Activities ◽  
Rabbit Aorta ◽  
Terminal Group ◽  
Intrinsic Activity ◽  
Duration Of Action ◽  
Receptor Sites ◽  
Oil Immersion ◽  
A Minor

The C-terminal group of angiotensin II (ATII), 1-Sar-ATII, and 1-β-Asp-ATII was esterified to reduce degradation of the peptides by carboxypeptidases.Biological activity of esterified angiotensins was measured in vivo (rat blood pressure) and in vitro (rabbit aorta strip). Degradation in vitro by purified carboxypeptidase was estimated from the intensity of the phenylalanine spot on paper chromatography. Disposition of esterified angiotensins by rabbit aorta strips was studied with the oil immersion technique of Kalsner and Nickerson, Can. J. Physiol. Pharmacol. 46, 719–730, (1968a).The results indicate that esterification of C-terminal group of ATII: (a) reduces the potency in vivo and to a greater extent the affinity in vitro; (b) delays the onset of the contraction in vitro; (c) does not affect the intrinsic activity; (d) prolongs the time of relaxation of rabbit aorta strips in oil; (e) prevents the degradation by purified carboxypeptidase.It is proposed that C-terminal group of ATII contributes to affinity but not to intrinsic activity and facilitates the diffusion of the peptide to receptor sites. Esterification of this group prevents the degradation of the peptide by carboxypeptidases; accordingly, the duration of action in vivo is prolonged and the rate of relaxation of aortic strips in oil is reduced. When esterification of the C-terminal is combined with the replacement of Asp by β-Asp in position 1, no relaxation of aortic strips occurs after oil immersion. This suggests that carboxypeptidases, and to a minor extent aminopeptidases, are responsible for the inactivation of angiotensin by rabbit aorta.

Role of the N-terminal Amino Acid for the Biological Activities of Angiotensin and Inhibitory Analogues

1974 ◽  
Vol 52 (1) ◽  
pp. 39-49 ◽  
Author(s):  
D. Regoli ◽  
F. Rioux ◽  
W. K. Park ◽  
C. Choi
Keyword(s):  
Smooth Muscles ◽  
Rabbit Aorta ◽  
Intrinsic Activity ◽  
Vascular Smooth Muscles ◽  
Terminal Amino Acid ◽  
Duration Of Action ◽  
Metabolic Degradation ◽  
Terminal Amino

Aspartic acid was replaced in position 1 of angiotensin II (ATII) with several amino acids, to assess the possible influence of the N-terminal amino acid for (a) the intrinsic activity, (b) the affinity, and (c) the metabolic degradation of agonist analogues of ATII. Some of the substitutions in position 1 were used in combination with replacement of Phe by Gly or Leu in position 8, to obtain the corresponding antagonist.The compounds were tested in vivo (rat blood pressure) and in two in vitro preparations (rat stomach and rabbit aorta strips). The oil immersion technique, described by Kalsner and Nickerson (1968) (Can. J. Physiol. Pharmacol. 46, 719–730), was used to study the disposition of the peptides by vascular smooth muscles (rabbit aorta strips). Degradation of the peptides by purified aminopeptidases was evaluated in vitro by measuring the fragments on paper chromatography. Potency of antagonists was estimated in vivo (ID50) and in vitro (pA2 values): duration of action was established by infusing the inhibitors intravenously into anesthetized rats and testing the effect of standard doses of angiotensin before and after.The results indicate that replacement of Asp with other amino acids does not influence the intrinsic activity, but can either increase or decrease the affinity in vitro or the potency in vivo. 1-Sar-ATII, and 1-D-Ala-ATII are more potent and longer acting than 1-Asp-ATII on isolated intestinal and vascular smooth muscles, but not in vivo. On the contrary, 1-β-Asp-ATII and 1-β-D-Asp-ATII are more potent than 1-Asp-ATIIin vivo, but not on rabbit aorta strips. Rate of relaxation of rabbit aorta strips suspended in oil, after contraction with submaximal doses of several analogues of ATII, are significantly slower than relaxation after 1-Asn2-ATII and 1-Asp-ATII. A close parallelism between the diminution of the relaxation rate in oil and the degradation by aminopeptideses in vitro was observed, suggesting that metabolic degradation may be the major factor determining relaxation of rabbit aorta in oil after contraction with one of these peptides. Potencies of antagonists in vivo and in vitro are increased by replacing Asp with Sar. Substitution of Asp with β-Asp or β-D-Asp brings about a slight increase of potency in vivo but not in vitro. It appears that firm binding and prolonged occupation of receptors by sarcosyl derivatives are the primary factors contributing to increase the potency and to prolong the duration of action of antagonists, while prevention or reduction of metabolic breakdown by aminopeptidases is much less efficient.

Biological activities of kinins and substance P octapeptides (4–11) in which phenylalanine residues have been replaced with L-carboranylalanine

1979 ◽  
Vol 57 (12) ◽  
pp. 1437-1442 ◽  
Author(s):  
R. Couture ◽  
J. -N. Drouin ◽  
O. Leukart ◽  
D. Regoli
Keyword(s):  
Biological Activity ◽  
Amino Acid ◽  
Substance P ◽  
Marked Reduction ◽  
Biological Activities ◽  
Chemical Modifications ◽  
Duration Of Action ◽  
Aromatic Residues ◽  
Prolonged Duration ◽  
Long Acting

The boron-containing amino acid carboranylalanine (Car) has been used for replacing the phenylalanine residues of bradykinin (BK), des-Arg9-BK and octa (4–11)-substance P (octa (4–11)-SP), in order to determine how the increased size and hydrophobicity of the aromatic residues will affect the biological activities of these peptides. Analogues of BK and of octa (4–11)-SP containing Car instead of Phe in positions 5 and 8 (BK) or 7 and 8 (octa (4–11)-SP) are practically inactive. A similar marked reduction of activity is observed with [Car8]-des-Arg9-BK, while [Car5]-des-Arg9-BK, although less potent than the natural BK fragment, shows a prolonged duration of action. Car has also been used to replace Phe5 in combination with the substitution of Phe8 by a Leu in the sequence des-Arg9-BK, in order to prolong the duration of action of antagonists for the B1 receptor of kinins. Moreover, a Lys has been added at the N-terminal of this sequence for further improving the affinity of the antagonism. The two chemical modifications have not produced the expected additive change of biological activity but a potent long-acting antagonist has been obtained with [Lys1,Car6,Leu9]-des-Arg10-BK.It is concluded that Car is unsuitable for replacing the phenyl residues of BK and octa (4–11)-SP, and also Phe8 of the fragment sequence des-Arg9-BK; Car appears, however, to be of some utility when used to replace Phe5 of the same sequence, as it prolongs the duration of action of agonists and of antagonists acting on the B1 receptor for kinins.

An Overview on Steroids and Microwave Energy in Multi-Component Reactions towards the Synthesis of Novel Hybrid Molecules

2020 ◽  
Vol 17 (8) ◽  
pp. 594-609
Author(s):  
Preetismita Borah ◽  
Vhatkar Dattatraya Shivling ◽  
Bimal Krishna Banik ◽  
Biswa Mohan Sahoo
Keyword(s):  
Energy Consumption ◽  
Multicomponent Reactions ◽  
Biological Activities ◽  
Vital Role ◽  
Microwave Energy ◽  
Biosynthetic Pathways ◽  
Chemical Transformations ◽  
Carbon Carbon Bond ◽  
Hybrid Molecules ◽  
Time Required

In recent years, hybrid systems are gaining considerable attention owing to their various biological applications in drug development. Generally, hybrid molecules are constructed from different molecular entities to generate a new functional molecule with improved biological activities. There already exist a large number of naturally occurring hybrid molecules based on both non-steroid and steroid frameworks synthesized by nature through mixed biosynthetic pathways such as, a) integration of the different biosynthetic pathways or b) Carbon- Carbon bond formation between different components derived through different biosynthetic pathways. Multicomponent reactions are a great way to generate efficient libraries of hybrid compounds with high diversity. Throughout the scientific history, the most common factors developing technologies are less energy consumption and avoiding the use of hazardous reagents. In this case, microwave energy plays a vital role in chemical transformations since it involves two very essential criteria of synthesis, minimizing energy consumption required for heating and time required for the reaction. This review summarizes the use of microwave energy in the synthesis of steroidal and non-steroidal hybrid molecules and the use of multicomponent reactions.

scholarly journals Insights into the Chemical Discovery of Remifentanil

2020 ◽  
Vol 132 (5) ◽  
pp. 1229-1234 ◽  
Author(s):  
Paul L. Feldman
Keyword(s):  
Analgesic Efficacy ◽  
American Chemical Society ◽  
Hepatic Function ◽  
Chemical Society ◽  
Opioid Agonist ◽  
Duration Of Action ◽  
Design Synthesis ◽  
Long Acting

Abstract Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission. In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure–activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

scholarly journals Piritramide—A New Long-acting Analgesic

1973 ◽  
Vol 1 (4) ◽  
pp. 308-314 ◽  
Author(s):  
David B. Gibb ◽  
Nicholas Pikler
Keyword(s):  
Nausea And Vomiting ◽  
Double Blind Trial ◽  
Double Blind ◽  
Duration Of Action ◽  
Blind Trial ◽  
Long Acting

Piritramide is a synthetic analgesic of the piperidine group. Reports indicate that it is a potent, long-acting drug and that the incidence of nausea and vomiting following its administration is very low. In this series of 60 cases piritramide 15 mg was compared with morphine 10 mg in a double-blind trial. The drug was found to have a potency similar to that of morphine and a mean duration of action of greater than 6½ hours (morphine 4 ½ hours). The incidence of nausea and vomiting was low with both drugs and piritramide appeared to exert a slight anti-emetic effect.

The Pressor and Myotropic Effects and the Antagonistic Properties of Several Analogues of Angiotensin II

1972 ◽  
Vol 50 (2) ◽  
pp. 99-112 ◽  
Author(s):  
D. Regoli ◽  
W. K. Park
Keyword(s):  
Angiotensin Ii ◽  
Chemical Structure ◽  
Biological Activities ◽  
Unnatural Amino Acid ◽  
Intrinsic Activity ◽  
Rat Stomach ◽  
Response Curves ◽  
Isolated Organs ◽  
The Right ◽  
The Relationship

The substitution of an unnatural amino acid, 1-aminocyclopentanecarboxylic acid (Acpc), for each of the eight amino acids of angiotensin (AT) has been used to study the relationship between chemical structure and biological activities of angiotensin. The pressor and the myotropic activities of the various ATII derivatives have been tested on the rat blood pressure and on three isolated organs: rat isolated colon, rat stomach strip, and rabbit isolated kidney.The results indicate that 6-His and 8-Phe are essential for the activities of angiotensin II. Moreover, (8-Acpc)-ATII, but not (6-Acpc)-ATII, antagonizes the pressor and myotropic effects of ATII and ATI. αE and pD2 of all analogues have been estimated on the isolated rat stomach strip to evaluate intrinsic activity and affinity for the receptors. (1-, (2-, (3-, (4-, and (5-Acpc)-ATII have the same intrinsic activities as ATII, while those of (6-, (7-, and (8-Acpc)-ATII are much lower.Analogues of ATII substituted in position 8 antagonize specifically the myotropic and pressor effects of ATII and ATI. On the contrary, the effects of other smooth muscle stimulating agents (acetylcholine, 5-hydroxytryptamine, bradykinin, and vasopressin) are not modified.Log dose response curves of ATII and ATI are shifted to the right in the presence of antagonists, but remain parallel. The antagonism is rapidly reversible and may be competitive.

Anabolic effects of the beta 2-adrenoceptor agonist salmeterol are dependent on route of administration

1994 ◽  
Vol 267 (3) ◽  
pp. E475-E484 ◽  
Author(s):  
N. G. Moore ◽  
G. G. Pegg ◽  
M. N. Sillence
Keyword(s):  
Soleus Muscle ◽  
Body Weight Gain ◽  
Route Of Administration ◽  
Duration Of Action ◽  
Routes Of Administration ◽  
Adrenoceptor Agonists ◽  
Slow Twitch ◽  
Beta 2 ◽  
Long Acting

It is reported that a long duration of action is required for beta 2-adrenoceptor agonists to evoke an anabolic response. In the present study, we compare the potency of clenbuterol with that of the new long-acting compound salmeterol, when given at equimolar doses to female Wistar rats by different routes of administration. Given orally for 10 days, salmeterol had no effect on growth at a dose of 120 micrograms/day, whereas at 2.4 mg/day the drug caused significant increases in body and carcass weight and in the mass of the mixed-fiber gastrocnemius/plantaris and tibialis anterior muscles, but there were no increases in the slow-twitch soleus muscles. A similar growth response was seen when clenbuterol was given orally at a dose of only 97 micrograms/day, with an additional response seen in soleus muscle at 1.9 mg/day. Thus clenbuterol was more potent than salmeterol when given by this route of administration. When the drugs were infused by osmotic minipump, both salmeterol (130 micrograms/day) and clenbuterol (100 micrograms/day) caused increases in body weight gain and in the weights of the mixed-fiber muscles, with the most dramatic effect of infusion being to greatly increase the anabolic effect of salmeterol in soleus muscle. A single intraperitoneal injection of salmeterol (53 micrograms) or clenbuterol (40 micrograms) caused a similar rapid increase in the concentration of adenosine 3',5'-cyclic monophosphate in gastrocnemius muscle. These results indicate that the potency of salmeterol in vivo is dependent on its route of administration and that slow-twitch muscles are less sensitive than mixed-fiber muscles to the anabolic effects of beta 2-adrenoceptor agonists.

Myotropic affinities of angiotensin II and des-Asp1-angiotensin II in rabbit aorta and femoral artery by microassay

1979 ◽  
Vol 57 (11) ◽  
pp. 1256-1266 ◽  
Author(s):  
William H. Waugh ◽  
Theodore E. Bales
Keyword(s):  
Angiotensin Ii ◽  
Femoral Artery ◽  
Rabbit Aorta ◽  
Mass Action ◽  
Intrinsic Activity ◽  
Angiotensin Receptors ◽  
Response Curves ◽  
Contractile Responses ◽  
Increased Sensitivity ◽  
Dose Dependent

Dose-dependent isometric contractions to [Asp1,Ile5]-angiotensin II (AII) and des-Asp1-[Ile5]-angiotensin II (AIII) were obtained with 3-mm-wide rings of rabbit thoracic aorta and femoral artery in microbaths. A period of 2.5–3 h was required to obtain reproducible contractile responses of increased sensitivity. Contractions developed faster and they were much more forceful but less sustained in femoral arterial rings than in aortic rings. Noncumulative dose–response curves with AII and AIII were parallel and reached the same maximum. Peak contractile responses were linearly proportional to the receptor stimulation predicted from the mass action equation and the concept of intrinsic activity relating bath dosage of agonist to the number of myotropic receptors occupied by AII and by AIII. These findings validated measurement of the myotropic affinities of both tissues for AII and AIII by the obtained ED50 values. In 0.6-mL baths, developed with the use of a meshed screen for reoxygenation, the apparent affinities of aortic muscle for AII and AIII averaged 0.149 and 0.0030 nM, respectively. The mean affinities were much greater at 0.594 and 0.236 nM, respectively, in femoral arterial muscle. The myotropic affinity for AIII relative to that for AII averaged 2.26% in the aorta but 40.8% in the femoral artery. The apparent affinities were reduced and contractions less forceful in 0.24-mL baths without regassing. The results suggest that AII and AIII may stimulate the same angiotensin receptors in aorta and femoral artery and that the receptors may be different in structure or immediate environment in these two vascular tissues.

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