Stereochemical Structure-Activity Relationships

Items 1 and 2 have been established chiefly by nmr ( H and 13C) studies for solutes and X-ray crystallography for solids. All data on optically active forms are due to the elegant work of Portoghese and his colleagues, who eludicated absolute configurations chiefly by correlations with or conversions to chiral molecules of known stereochemistry. 

Turning now to derivatives with substituents adjacent to nitrogen, the racemic a-and /3-2-methyl-reversed esters prove to have similar activities (in contrast to the prodine diastereoisomers) and are somewhat less potent than the parent desmethyl derivative (see 17)/23 The /3-2-methylpropionate, with 

Reversed esters with equatorial methyls adjacent to both 4-phenyl (as in a-prodine) and nitrogen (as in 17) are next considered. The activity of the racemic y-2,5-dimethyl derivative mixture (promedol, trimeperidine), of like potency to the unsubstituted reversed ester, proves to reside chiefly in the (+)-isomer of 2S,4S,5R configuration (see 15).(49 Note that the methyls are 

in 2- and 3-monomethyl, and 2,5- and 2,3-dimethyl derivatives with preferred equatorial hydrocarbon substituents, consistent and additive stereochemical structure-activity relationships are found. Furthermore, the more active antipodal forms have potencies close to that of the desmethyl parent ester, in support of an essentially passive role for methyl substituents of this type in the drug-receptor interactions. 

From the viewpoint of preferred conformation a stereochemical correlation between the more potent antipodal forms of /3-prodine and the a-2,5-dimethyl derivative (a-promedol) is not immediately apparent. In the latter compound the dextro isomer, depicted in its axial 4-phenyl chair form (preferred for a-4-piperidinol base, X-ray evidence)/38 is about 20 times more active than the desmethyl parent while the levo form is inactive (see 22). sl) The inverted chair form of (+)-a-promedol (23) clearly reveals a stereochemical kinship with (+)-/3-prodine in respect to C-3(5) geometry, and furthermore points to the activity-raising role of axial methyl adjacent to nitrogen when 

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Some novel experimental results are in contradiction to the hypothesis of a stereochemical structure-activity relationship. Two research groups (Corey et al., Tacke, Wannagat et al.) are working independently from each other on silicon containing tricyclic compounds with potential psychotropic activity, to bring some light to this dilemma. 

QSSAR Quantitative stereochemical structure-activity relationship MM2 Molecular mechanics force field... 

KimuraY, Atarashi S, Kawakami K, Sato K, Hayakawa I (1994) Fluorocyclopropyl)quino-lones. 2. Synthesis and stereochemical structure-activity relationships of chir2il 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-l-(2-fluorocyclopropyl)quinolone antibacterial agents. J Med... 

The first chapter deals with metabolic factors affecting the biological activities of androgens. In the second chapter the structure-activity theories are reviewed. A new approach to the structure-activity relationship is offered in Chapter 3. The effects of structural and stereochemical changes on biological activities are extensively analyzed in this chapter. A new theory of steroid-receptor interaction concludes this chapter. 

Mechoulam, R. Lander, N. Srebnik, M. Breuer, A. Segal, M. Feigenbaum, J.J. Jarbe, T.U.C. Consroe, P. Stereochemical Requirements for Cannabimimetic Activity in Structure-Activity Relationships of the Cannab-inoids NIDA Research Monograph Series 79. 

Leading concepts of the nature of the analgesic receptor, as well as pertinent stereochemical studies of narcotic analgesics, have been reviewed by Portoghese. Differing modes of drug-receptor association and the phenomenon of Induced fit are favored as possible explanations for some of the complexities that characterize structure-activity relationships In this field. 

The total synthesis of nakienone A was reported by Negishi in 1997. Negishi s synthesis used a Pd-mediated cross-coupling reaction to install the pentadiene functionality on the cyclopentene ring. The total synthesis not only proved the original stereochemical determinations to be correct but also represented a facile method for the synthesis of the entire series of natural compounds as well as analogues for structure activity relationship (SAR) studies. 

The pharmacology of Cannabis, and, in the last 20 years, of A -THC, has been the object of thousands of publications and has been thoroughly reviewed. Most of the work has centered on the cannabimimetic effects in man as well as in various animal species. As the cannabimimetic effect has no medicinal value, we shall refrain from a detailed recapitulation of the well-reviewed material on this particular aspect. We would like to refer the reader to some recent reviews as well as to several older, critical, thoughtful and surprisingly topical reviews by Sir W.D.M. Paton and his colleagues from 1973 and 1975 [3-8, 52-61]. In the present review, we shall address ourselves to and summarize only four aspects related to cannabimimetic action (a) pharmacological test methods (b) structure-activity relationships (SAR) (c) stereochemical requirements and (d) recent approaches to the biochemical basis of cannabimimetic action. 

In the study of essential oils, the separation and isolation of the individual chemical constituents is critical in understanding the origin of the biological activity of these oils. This process also can eliminate undesirable compounds such as colorants and other materials, which may impart toxicity or have a detrimental effect on the biological activity or quality of the essential oil products. In follow-up studies, complete structural determination, in particular the relative and absolute stereochemical assignments, is critical for a complete understanding of the active compounds and their structure-activity-relationships. In this section, a brief general review of separation, isolation, and structure determination methods will be discussed. 

As part of a medicinal chemistry program [16] directed toward discovering new muscarinic receptor ligands, a series of endo- and exo-2-alkyl-2-aza-bicyclo[2.2.1]heptan-5-ol (38 and 39) and endo- and exo-2-alkyl-2-aza-bicyclo[2.2.1]heptan-6-ol (40 and 41) esters have been synthesized from 2-alkyl-2-azabicyclo[2.2.1]heptan-5-enes (Scheme 2.4). Oxidation of the olefin and stereochemical manipulation of the secondary alcohols followed by esterification of the azanorbornene products provided the different isomers required for systematic investigation of the structure-activity relationships of this structural series. 

Bentley and his colleagues7 describe the structure-activity relationships of a wide variety of structures derived from Diels-Alder adducts of thebaine. Among this group are found some of the most potent analgesics known. Particular attention should be directed toward the fine application of nuclear magnetic resonance spectroscopy, by Fulmor and his associates to elucidate the stereochemical configurations of these interesting compounds. 

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