Biomedical subjects
Publications and source records attributed to A Giachetti.
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Replacement of the glycine in position 8 of the C-terminal heptapeptide NKA(4-10) with beta-alanine give rise to a potent and selective agonist for the NK-2 tachykinin receptor. The affinity of [beta-Ala8]-NKA(4-10) to the NK-2 receptor is enhanced by almost one order of magnitude as compared to NKA(4-10), while affinity decreases at about the same extent at NK-1 and NK-3 receptors, respectively. Synthesis and biological activities of a series of NKA(4-10) analogues systematically replaced in each position with beta-alanine are also reported.
By introducing D-Trp in position 6 and 8 along with pyroglutamic acid (Pyr) in position 4 or Nle in position 10 of NKA(4-10) we have obtained selective although weak NK-2 tachykinin receptor antagonists. Similar substitutions, previously reported on the sequence of SP, gave rise to nonselective antagonists presumably for the limited selectivity of the agonist used as template. Further modifications like the addition of a third D-Trp in position 9 gave rise to more potent but less selective antagonists, thus showing that each amino acid substitution can dramatically affect selectivity.
We have developed a novel series of peptides, related to the NKA(4-10) sequence, in which substitution of selected amino acids determined variations in the affinity for the TK receptor subtypes. Subcutaneous pretreatment of rats with some peptides of this series reduced gastric ulcers induced by ethanol, indomethacin or acetylsalicylic acid (ASA) as well as duodenal ulcers induced by dulcerozine. In particular [Ala5]NKA(4-10) and [Ala5,beta Ala8]NKA(4-10) possess a broad spectrum of antiulcer activity which is long lasting and stronger than the precursor NKA(4-10). The observation that the prevention of ethanol-induced gastric lesions could be reversed by pretreatment with indomethacin favors the possible involvement of prostaglandins in the observed gastroprotection by TK analogs.
The role of the D-Trp residues in the sequence of the NK2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2). has been examined by replacement of each D-Trp with either the L-isomer or the residue naturally occurring in the same position of neurokinin A(4-10). The biological activity of the analogues thus obtained has been characterized, with special attention to the selectivity for the three tachykinin receptors and for the two subtypes of the NK2 receptor recently described. We conclude that the simultaneous presence of the three D-Trp residues of MEN 10207 is crucial both for affinity and for selectivity.
The role of the C-terminal residue in the sequence of the NK-2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2), has been examined by systematic amino acid substitutions. Biological activity has been measured on two in vitro preparations chosen as paradigms of the recently described NK-2 receptor subtypes, namely the rabbit pulmonary artery and the hamster trachea, in order to define the structural requirements necessary for antagonist subtype selectivity. We conclude that in the presence of a C-terminal hydrophilic residue, affinity is maximal for the NK-2A subtype, while hydrophobic, bulky and aromatic residues increase affinity for the NK-2B subtype.
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beta-Adrenoceptors were labeled with the selective beta-antagonist (-)[3H]dihydroalprenolol ([3H]DHA). Cardiac membranes isolated from renal hypertensive rats had the same density of adrenoceptors as normotensive rats (28 fmoles/mg of protein in both groups) but showed a significant elevation of the dissociation constant for [3H]DHA (Kd = 1.86 nM versus 1.04 nM for controls), indicating a reduced affinity of cardiac adrenoceptors for the radioligant. The lowered sensitivity to catecholamine is probably due to chronic exposure of beta-receptors to a high concentration of noradrenaline, whose turnover in cardiac nerves of renal hypertensive rats was significantly accelerated (turnover time 10.5 hr for hypertensive versus 17.2 for normotensive).
Conditioned initial freezing duration was timed in the light-dark box test. Four genetically diverse groups of rats (Wistar, Long Evans, Brattleboro heterozigous for diabetes insipidus, Brattleboro homozygous for diabetes insipidus) were employed. 0.6 mA and 1.8 mA footshocks were administered as nociceptive stressors. The results showed that freezing duration easily and conveniently measures the animal's capacity of responding to stress. This finding is discussed in terms of genetically determined hormonal make-up and of CNS receptorial mechanisms. Initial freezing duration is proposed as a tool to evaluate stress responses.
Parotid saliva secretion was studied in conscious dogs in which a chronic fistula of the parotid duct was provoked by a simple surgical procedure. To validate the technique employed, the responsiveness of the gland to various stimuli was examined. The volume of secretion was measured as well as the concentrations of Na+, K+ and calcium. Secretion was elicited by administering bethanechol i.v. or by feeding a meat meal. These stimuli, applied repetitively in the same animal, evoked reproducible secretory responses. In addition, the dose-response curve to bethanechol could also be constructed. The parotid secretion is controlled by muscarinic receptor activation, as illustrated by atropine blockade and its insensitivity to adrenergic drugs. The preparation is a versatile model which allows to investigate secretion evoked by both direct and reflex activation. The advantages of the preparation, which avoids invasive techniques, are accurate measurements and reproducible responses over long periods in a conscious animal.
The pharmacological effects of the novel compound WEB 1881 FU (4-amino-methyl-1-benzyl-pyrrolidine-2-one-fumarate) were investigated. The tests performed indicate that the compound has cytoprotective as well as metabolism and cognition enhancing and central cholinomimetic properties. The nootropic effects in all tests were more pronounced than those of piracetam, while the central cholinomimetic effects were generally weaker than those of directly acting cholinomimetic agents. However, the typical peripheral cholinergic side effects were not observed. From the results we believe that the stimulating effect of WEB 1881 FU upon the central cholinergic system is modulatory rather than direct. The combination of nootropic and cholinomimetic properties appears favorable for treatment of brain dysfunction in the elderly. Side effects are less serious than with other known cholinomimetics.
Idrapril is the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors. Its pharmacokinetics and pharmacodynamics (plasma ACE activity) were investigated in rats, dogs (after intravenous and oral doses), and human volunteers (after oral doses). Following intravenous administration (1 mg/kg) to rats and dogs, elimination half-lives were 96 and 52 min, systemic clearance 19.6 and 9.5 ml/min kg, and volume of distribution 2.7 and 0.8 liters/kg, respectively. Pharmacokinetics appeared linear in dogs, within the dose range of 0.1-10 mg/kg. After oral administration of similar doses (approximately 2 mg/kg) in the three species studied, peak plasma concentrations were 182, 567, and 726 ng/ml; AUCs 25, 85, and 182 micrograms min/ml; and elimination half-lives 82, 54, and 174 min in rats, dogs, and healthy volunteers, respectively. Absolute oral bioavailability was calculated to be approximately 24% in rats and dogs. Idrapril did not bind to plasma proteins of the species studied. Plasma ACE was fully inhibited following oral administration of approximately 2 mg/kg in rats and humans, but in dogs maximal inhibition did not exceed 85%. Duration of action, measured as time for ACE to recover to 70% of initial activity, was approximately 5, 3, and 22 hr in rats, dogs, and humans, respectively. Idrapril plasma levels appeared correlated in a saturable way with inhibition of plasma ACE in all three species, yielding ex vivo IC50 values of approximately 7 ng/ml for both the rat and humans, and 91 ng/ml for dogs.