Nitric Oxide Synthase Inhibition by Pentacycloundecane Conjugates of Aminoguanidine and Tryptamine

• Published in: Archiv der Pharmazie (Weinheim) Vol. 342; no. 2; pp. 73 - 79
• Main Authors: Wilkes, Dennis K., de Vries, Armand, Oliver, Douglas W., Malan, Sarel F.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-02-2009; WILEY‐VCH Verlag
• Subjects: Aminoguanidine; Animals; Brain - drug effects; Brain - enzymology; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - pharmacology; In Vitro Techniques; Inhibitory Concentration 50; Male; Molecular Structure; Nitric oxide synthase; Nitric Oxide Synthase - antagonists & inhibitors; Pentacycloundecane; Rats; Rats, Sprague-Dawley; Tryptamine; Tryptamines - chemical synthesis; Tryptamines - chemistry; Tryptamines - pharmacology
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200800198

This paper describes the synthesis and in‐vitro activity of pentacycloundecane‐conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine‐derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC50 values of aminoguanidine (IC50 = 2.306×10–3 M) and 8‐imino‐N‐guanidino‐pentacyclo‐undecane 2 (IC50 = 8.803×10–5 M) revealed a more than 26‐fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3‐hydroxy‐4‐[3‐(2‐aminoethyl)indole]‐azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane 4 and 8‐[3‐(2‐aminoethyl) indole]‐pentacyclo[5.4.02,6.03,10.05,9]undecane 7 showed the best activity of the tryptamine analogues with a more than 3‐fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors.