Rigidification

Up till now, we have considered minor adjustments of functional groups on the periphery of the morphine skeleton or drastic simplification of the morphine skeleton. 

A completely different strategy is to make the molecule more complicated or more rigid. This strategy is usually employed in an attempt to remove the side-effects of a drug or to increase activity. 

It is usually assumed that the side-effects of a drug are due to interactions with additional receptors other than the one we are interested in. These interactions are probably due to the molecule taking up different conformations or shapes. If we make the molecule more rigid so that it takes up fewer conformations, we might eliminate the conformations which are recognized by undesirable receptors, and thus restrict the molecule to the specific conformation which fits the desired receptor. In this way, we would hope to eliminate such side-effects as dependence and respiratory depression. We might also expect increased activity since the molecule is more likely to be in the correct conformation to interact with the receptor. 

The best example of this tactic in the analgesic field is provided by a group of compounds known as the oripavines. These structures often show remarkably high activity. 

The oripavines are made from an alkaloid which we have not described so far— thebaine (Fig. 12.26). Thebaine can be extracted from opium along with codeine and 

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Alternatively, rigidification of the y-peptide backbone to avoid H-bonds between nearest neighbors can be achieved by the introduction of an a,y9-unsaturation into the backbone of each y-amino acid constituent (vinylogous peptides) ]208, 209]. Recent ab-initio calculations suggested that the a,/9-unsaturated y-peptide backbone might support the formation of helices with large 19- and 22-membered H-bonded pseudocycles ]221]. 

It should be pointed out that 0H5in is involved in RNA recognition [21-26] and might also have an influence on the enzymatic inactivation of the antibiotics. Since cyclization of neomycin-B to give 2 or 3 required the removal of this OH group, the deoxy- derivatives 5 and 6 were also synthesized as controls, in order to isolate the effect of rigidification. 

Li, Y., Chung, T.S., Cao, C., and Kulprathipanja, S. (2005) The effects of polymer chain rigidification, zeolite pore size and pore blockage on polyethersul-fone (PES)-zeolite A mixed matrix membranes./. Memhr. Sci., 260, 45-55. 

Fig. 9.8 Evolution of a fragment from Tethering with extenders to a potent caspase-3 inhibitor. Simple replacement of the disulfide linker with an alkyl linker resulted in a low micromolar inhibitor (4), and rigidification (5) and functionalization (6) of this linker led to increasingly potent inhibitors. The salicylic acid hit itself (7) had no detectable binding.

In principle every compound with an amino and a carboxy group can be used for such purpose ranging from simple co-amino acids [e.g., 5-aminopentanoic acid (6-aminovaleric acid) (1, n = 3)]1541 or 6-aminohexanoic acid (e-aminocaproic acid) (1, n = 4)]135,57,4 791 and related derivatives of 3-aminobenzoic acid 14801 or more sophisticated structures. A few examples (1-6) are shown in Scheme 28. Numerous cyclic turn mimetics have been developed in the past years and for details on this subject the reader is directed to Vol. E 22c, Section 12. To explore the rigidification introduced by nonnatural amino acids or equivalent structures into cyclic peptides, a careful NMR conformational analysis is required, since frequently the so-called p-turn mimetics do not enable such turns to be established, conversely other secondary structure elements may be induced.14811... 

The rigidif ed thermoplastic sheet process combines thermoplastic sheet vacuum forming with a spray-up or cold press molding process to add a thermoset composite structural backing to a decorative thermoplastic skin. Large parts such as bathtubs, hot tubs, recreation vehicle components, and camper tops have been produced by this process. 

The diboronic acids 23 and 24 form rigid cyclic complexes with chiral monosaccharides and disaccharides this is the origin of the CD observations. The induced chirality upon formation of rigid, chiral complexes was monitored by CD spectroscopy, and this rigidification process can be utilized in the design of spectroscopic... 

The process of rigidification has been extended, especially by Cannon s group, to include a large series of cis and trans fused octahydrobenzo[f] and octahydrobenzo[g]quinolines. Cannon et al. (27) recently summarized this work. It is certainly clear that incorporation of dopamine into a rigid framework can alter both specificity and potency. However, suitable explanations for some of the observed activities are still lacking. For example, the octahydrobenzo[g]quinoline XV (R=H or n-propyl) is inactive in the renal DA- receptor (27). No one has so far been able to explain why this is so, although a receptor model is offered later is this paper which can accommodate this finding. 

The concept of alpha and beta rotameric forms of DA is covered in the section on rigidification. A summary of some recent findings in this area together with details of the X-ray structure of 6,7-ADTN has also been published by the present author (15). In connection with the above topic our group has published quantitative details of the penetration and distribution of DA agonists into the CNS as well as the effect of COMT inactivation (16, 17,... 

The author mentions the work of Cannon who has carried out some of the best studies on the effects of rigidification of DA analogues. The latter compounds are certainly much better examples of this concept than compounds XII and XIII which are not really "rigid" but merely analogues with restricted conformational freedom. 

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