Restricted Analogues of

Over the years, our laboratory has generated a library of analogues of C5a 5 in which backbone flexibility was restricted by certain amino acid substitutions. This was done with the goal of biasing certain conformational features that might be helpful in the search for biologically relevant conformations responsible for the induction of C5a-like immunostimulatory activities versus those responsible for C5a-like inflammation. 

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GABAc receptors are defined by their insensitivity to bicuculline and their activation by conformationally restricted analogues of GABA such as CACA and (+)-CAMP (15, 2i -2-(aminomethyl)cyclopropanecarboxylic acid). They are blocked by picrotoxin but can be selectively antagonised by TPMPA (l,2,5,6-tetrahydropyridin4-ylphosphinic acid). Unlike GABAa receptors, they are not affected by benzodiazepines, barbiturates or anaesthetics (Barnard et al. 1998 Bormann 2000 Chebib and Johnston 2000). 

D Ambra K, Estep G, et al. Conformational restricted analogues of pra-vadoline nanomolar potent, enanantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor. J Med Chem 1992 35 124—135. 

To limit the structural flexibility of these two aromatic residues, conformationally restricted analogues of Phe and/or Tyr were substituted [28,30] (Fig. 1). 

Mallamo JP, Diana GD, Pevear et al. Conformationally restricted analogues of disoxaril. J Med Chem 1992 35 4690-4695. 

Dihydromuscimol (49) is a conformationally restricted analogue of the physiologically important neurotransmitter y-aminobutyric acid (GABA) and has been prepared using the cycloaddition of dibromoformaldoxime to A-Boc-allylamine followed by N-deprotection with sodium hydroxide (Scheme 6.52) (278). The individual enantiomers of dihydromuscimol were obtained by reaction of the bromonitrile oxide with (5)-( + )-l,2-0-isopropylidene-3-butene-l,2-diol, followed by separation of the diastereoisomeric mixture (erythro/threo 76 24), hydrolysis of respective isomers, and transformation of the glycol moiety into an amino group (279). 

A series of conformationally restricted analogues of nicotine and anabasine have been prepared as part of a program studying models of Parkinson s disease and pain (Scheme 8). Transformations of the heterocyclic ketone were key to the program, including cyclization to a third heterocyclic ring <1998BML2173>. 

Sham HL, Bolis G, Stein HH, Fesik SW, Marcott PA, Plattner JJ, Rempel CA, Greer J. Renin inhibitors. Design and synthesis of a new class of conformationally restricted analogues of angiotensinogen. JMed Chem 1988 31 284-295. 

Mullen G, Napier J, Balestra M, DeCory T, Hale G, et al. 2000. (-) -Spiro [ 1 -azabicyclo [2.2.2] octane-3,5 -oxazolidin-2 -one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha-7 nicotinic acetylcholine receptor. J Med Chem 43 4045-4050. 

Barboni, L. Lambertucci, C. Ballini, R. Appendino, G. Bombardelli, E. Synthesis of a conformationally restricted analogue of paclitaxel. Tetrahedron Lett., 1998, 39 7177-7180. 

Nakaie CR, et al. Inhibition of renin by conformationally restricted analogues of angiotensinogen. Biochem. J. 1982 205 43-47. 

Conformationally restricted analogues of lavendustin A were prepared by M. Cushman and co-wokers as cyctotoxic inhibitors of tubulin polymerization. ... 

O., Watkins, W.J., Ohta, T., Nakayama, K., and Ishida, Y. (2003) Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorganic Medicinal Chemistry Letters, 13 (16), 2755-2758. 

Musicki, B., and Vevert, J.-P., Synthesis of conformationally restricted analogues of an angiotensin II receptor antagonist. General synthetic approach to functionalized imidazo[l,5-a]pyridine derivatives, Tetrahedron Lett., 35, 9391, 1994. 

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