The synthesis of the tetrapeptides Ala-Gly-Gly-His, Boc-Ala-Gly-Gly-His (Boc = t-butoxycarbonyl), Ala-G ly-G ly-H is(n-bom) (x-bom = N"benzoxymethyl), Ala-Gly-G ly-H is-OMe, and Ala-Gly-Pro-H is is reported, together with the results of a pH-metric and spectroscopic (absorption, c.d., and e.s.r.) study of their complexes with H + and Cu". The work was designed to study the initial site of binding to Cu" in peptides containing both a terminal amino nitrogen and a histidyl residue. Results show that the n-N of the imidazole ring of the histidyl residue is the primary anchoring site for copper(it) co-ordination, and that the next nitrogen to bond can be the terminal amino N, forming a macrocyclic chelate ring.
The efficacy and the tolerance of milnacipran (100 mg/day), a second generation antidepressant which equipotently inhibits both noradrenaline and serotonin reuptake, was compared to fluoxetine (20 mg/day), a selective serotonin reuptake inhibitor, in two parallel groups of, respectively, 97 and 93 major depressive outpatients. The duration of the study was 6 weeks, with assessments every 2 weeks by means of the Montgomery and Asberg depression scale (MADRS), the Hamilton depression scale, the clinical global impressions (CGI), and a checklist of symptoms and side-effects. Results showed significant superiority of fluoxetine over milnacipran on most rating instruments: MADRS (P = 0.01) including five individual items, Hamilton depression scale (P = 0.002) including ten individual items, CGI of severity (P = 0.01) and therapeutical index (P = 0.002). On visual analogue scales assessing the clinical profile of the compounds, fluoxetine was rated as exhibiting more psychostimulating activity than milnacipran (P = 0.0008). The tolerance of the two antidepressants was very similar, with the exception of symptoms of dizziness which were more frequently reported with milnacipran (P = 0.01). These differences in efficacy favoring fluoxetine could result from the selection of a dose of milnacipran below the optimal therapeutic dose for this type of psychiatric patients or to the administration of the compounds in single daily intakes, whereas milnacipran possesses a plasma elimination half-life of only 7 h.
The L-proline residue in oligopeptides has been shown to act as a 'break-point' in their co-ordination to copper(ii) ions leading to the formation of large chelate rings with the peptide locked in the (3-conformation.
Results are reported of a potentiometric and spectrophotometric study of the H + and Cu2+ complexes of the tetra peptides X-Gly-Gly-G ly, G ly-X-G ly-Gly, G ly-Gly-X-G ly, and Gly-Gly-G ly-X where X is the proline (Pro) and sarcosine (Sar) residue (Gly = glycine). All the tetrapeptides (HL) form the series of complexesand [CuH-,L] (charges omitted). The ligands Gly-X-Gly-Gly also form the bis-complex, [CuL,]. When inserted in a peptide chain the Pro and Sar residues cannot co-ordinate t o Cu2+ through their peptide nitrogens since they d o not possess ionizable protons. In addition the Pro residue tends t o force the peptide chain to form a 'pturn' and so adopt a 'bent' conformation. These studies demonstrate the formation of a large chelate ring when tetrapeptides containing Pro (and, to a smaller extent, Sar) in the second or third positions co-ordinate t o Cu2+. This ring spans the terminal residues of the peptide chain and locks the peptide into a 'bent' or 'horse-shoe' shaped conformation. Cu2+ could therefore play an important role in activating oligopeptides (e.g. neuropeptides) containing proline.
The tetrapeptides Phe-Gly-Pro-Phe, Phe-Gly-Pro-Tyr, and Tyr-Gly-Pro-Phe have been synthesised and their complexes with H + and Cu2+ studied b y potentiometry and spectroscopy (u.v., visible, c.d., and e.s.r.) at 25 "C and I = 0.1 0 mol dm-3 (KNO,). The results show that with both tetrapeptides containing the Tyr residue, Tyro--Cu bonding is present at p H > 8. With Tyr-Gly-Pro-Phe this is achieved through the formation of dimeric complexes while with Phe-Gly-Pro-Tyr a monomeric complex with a large chelate ring is formed.
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