Biologically-active-prototypes

With the advent of computer-aided-drug modeling (CADM) the critical, scientific and faster approach to newer drug entities based on the biologically active prototypes, combinatorial chemistry, chiral chemistry and biotechnology has paved the way towards more specific, potent and above all less toxic drugs to improve the ultimate quality of life in humans. 

Under this method a new drug moleeule is developed from a biologically active prototype. The various advantages are as follows ... 

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

Reduced nicotinamide-adenine dinucleotide (NADH) plays a vital role in the reduction of oxygen in the respiratory chain [139]. The biological activity of NADH and oxidized nicotinamideadenine dinucleotide (NAD ) is based on the ability of the nicotinamide group to undergo reversible oxidation-reduction reactions, where a hydride equivalent transfers between a pyridine nucleus in the coenzymes and a substrate (Scheme 29a). The prototype of the reaction is formulated by a simple process where a hydride equivalent transfers from an allylic position to an unsaturated bond (Scheme 29b). No bonds form between the n bonds where electrons delocalize or where the frontier orbitals localize. The simplified formula can be compared with the ene reaction of propene (Scheme 29c), where a bond forms between the n bonds. 

Elucidation of the mechanism of action for virtually all biologically active substances has been a collaborative effort between scientists in a variety of disciplines. In the area of drug research, medicinal chemists have played important roles by providing series of homologs and congeners of prototype compounds. The development of potency series, where the in vivo action can be correlated with in vitro or biochemical effects, has often played a pivotal role in formulating hypotheses about mechanism of drug action at the molecular level. 

The chemical structures and biological activities of hundreds of opioid analgesics derived from the prototype opioid drug morphine are most comprehensively described in two books published in 1986, one entitled Opioid Analgesics, Chemistry and Receptors by Casy and Parfitt [1] and the other entitled Opiates by Lenz et al. [2]. Follow-up articles include those by Casy in 1989, entitled Opioid Receptors and their Ligands Recent Developments [3] which also includes sections on opioid peptides, affinity labelling and opioid receptor subtypes Rees and Hunter in 1990 [4] covering the... 

It was soon apparent that this compilation would become unmanageably large. The first major trimming was the elimination of the compounds that were synthetic, and the limitation of the listing to those compounds that have been reported as plant products. These isoquinolines could play the dual role of serving not only as potential contributors to the action of psychoactive plants but also as prototypes for the synthesis of new materials that might themselves be biologically active. 

In accordance with published and our own results the prostanoid analogues should show biological activity, when the entire molecule conformation does not differ greatly from that of natural prototype. 

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