Synthesis of N3-fumaramoyl-L-2,3-diaminopropanoic acid analogues,the irreversible inhibitors of glucosamine synthetase

Several analogues of N³-fumaramoyl-L-2,3-diaminopropanoic acid were synthesized and evaluated for inhibition of glucosamine-6-phosphate synthetase activity. The syntheses were accomplished by acylation reaction of N²-tert.-butoxycarbonyl-L-2,3-diaminopropanoic acid (Boc-A₂pr) or N²-tert.-butoxy-carbonyl-L-2,4-diaminobutanoic acid (Boc-A₂-bu) with the N-succinimidoyl esters of several derivatives of α, β-unsaturated acids 2a-d followed by deprotection of the Boc groups. The obtained compounds were tested for inhibition of glucosamine synthetase isolated from Salmonella typhimurium and Saccharomyces cerevisiae. The results indicated that among the synthesized compounds, N³-4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP) was the most powerful inhibitor of glucosamine synthetase.     

Surprising Pharmacological Activity of Analogues Designed by Substitution of Position 3 in Arginine Vasopressin (AVP) and 8-D-Arginine Vasopressin with l-2-Naphthylalanine

In an attempt to develop more active and selective analogues of arginine vasopressin (AVP), two peptides have been designed, synthesized and tested for vasopressor (V₁-receptors) and antidiuretic (V₂-receptors) activities. We also estimated the uterotonic and anti-uterotonic activities of these compounds in-vitro. The first peptide, [(l -2-Nal)³] AVP is a highly active V₂-agonist. The second analogue, [(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 V₁-antagonist devoid of anti-uterotonic activity. High antipressor potency of the second peptide was achieved without modification of position 1.     

Biologically active analogues of arginine vasopressin containing conformationally restricted dipeptide fragments

In this study we described the synthesis and pharmacological properties of five new analogues of arginine vasopressin (AVP). Four of these analogues contained ethylene-bridged dipeptide Phe-Phe in positions 2 and 3; one had two N-Me-Phe residues. All new peptides were tested for vasopressor and antidiuretic activities. We also estimated the uterotonic activities of these compounds in vitro. Three analogues were highly potent V₁-antagonists. One of them, namely [Cpa¹,(Phe-Phe)^2,3,Val⁴]AVP, which seemed to not interact with either V₂ and oxytocic receptors, was outstandingly selective. It is interesting that the high antipressor potency of our second peptide, [(N-Me-Phe)^2,3]AVP, was achieved without modification of position 1. Our results open new possibilities for the design of very potent and selective V₁-antagonists of AVP.     

Second messenger pathways in the modulation of neurotransmitter release

Activation of receptors on postganglionic sympathetic nerve endings can alter the amount of noradrenaline release during a train of nerve impulses. These changes may be produced by the enzyme-linked synthesis of second messenger molecules within the nerve terminal. Cyclic AMP analogues enhance noradrenaline release and two hormones adrenaline and ACTH appear to enhance noradrenaline release through activation of adenylate cyclase. Activation of the phospholipase C/protein kinase C pathway also elevates stimulation-induced noradrenaline release and angiotensin enhancement of noradrenaline release appears to act through this pathway. On the other hand, receptors which inhibit noradrenaline release (α₂-adrenoceptors, muscarinic Mi receptors and neuropeptide Y receptors) do not act through either of these signal transduction pathways. Since these inhibitory systems are neurotransmitter activated and relay information on a nerve pulse to nerve pulse time scale back to the nerve ending a fast activation and deactivation rate of modulation is required. This may be better served by direct modulation of ion channels without a slow intervening enzyme step. Activation of protein kinase C by phorbol esters produces relatively large increases (two-threefold) in stimulation-induced noradrenaline release and this enzyme may also have a physiological role. Protein kinase C may be an appropriate target for drugs to manipulate transmitter release and development of selective activators and inhibitors of the many protein kinase C isoenzymes may prove clinically useful in diseases with inappropriate transmitter release profiles.