Cocaine structure determination

Oxidation of ecgonine (2) by means of chromium trioxide was found to afford a keto acid (3). This was formulated as shown based on the fact that the compound undergoes ready themnal decarboxylation to tropinone (4)The latter had been obtained earlier from degradative studies in connection with the structural determination of atropine (5) and its structure established independently. Confirmation for the structure came from the finding that carbonation of the enolate of tropinone does in fact lead back to ecgonine. Reduction, esterification with methanol followed by benzoylation then affords cocaine. 

FIGURE 21.3 Action of class I and II cocaine-displaceable aptamers The effect of cocaine-displaceable aptamers 1-14 and II-3 on carbamoylcholine (lOOpM)-induced stimulation of acetylcholine receptor activity in the absence (control) and presence of cocaine was determined in vitro by fast kinetic electrophysiology. Aptamer 1-14 (0.5 pM) inhibited receptor activity (left panel) aptamer II-3 (5 pM) does not inhibit receptor activity (middle panel) aptamer II-3 (3 pM) alleviates inhibition of receptor function by cocaine (150 pM) (right panel). Prediction of the secondary structure [26] revealed the localization of consensus motifs of class-I and -II aptamers in stem-loop regions (letters in boxes). These stem loops are believed to be necessary for aptamer action. The figure reveals the data published in references [18, 19, 74]. 

For several thousand years, man has used herbs and potions as medicines, but it is only since the mid-nineteenth century that serious efforts were made to isolate and purify the active principles of these remedies. Since then, a large variety of biologically active compounds have been obtained and their structures determined (e.g. morphine from opium, cocaine from coca leaves, quinine from the bark of the cinchona tree). 

The all-atom RMSD between the molecular geometry of the structure determined in this work and the previously known structure of cocaine was found to be 0.069A, and Figure 12.18b shows the two structures superimposed. The unit cell dimensions all agree to within 2.3% and the volume difference between the two structures is 0.8% (3.29A per molecule). 

MACCS-II enables direct interface with other database management systems, such as the Relational Database Management System (RDBMS) and Oracle, so that databases which contain text and numeric data for which special interfaces are normally needed can be constructed. For example, an Oracle MACCS-II linked system is currendy being used by the National Institute on Dmg Abuse (113) to develop a database that will allow scientists to determine the molecular structures of cocaine and other controlled substances as well as designer dmgs. 

In 1898, Willstatter determined the correct structures of both atropine and cocaine. He followed this by synthesizing cocaine in 1901. 

As compounds l-9a-c (the front-bridged or the back-bridged structures — either isomer at C-6 or C-7) were more potent than cocaine, it seems that the orientation of the nitrogen lone pair is not a crucial determinant for high affinity binding, but can be of importance for the transporter... 

An unusual magnetic equivalence in the n.m.r. spectrum of N-benzoyl-norecgonine ester was observed, in contrast with cocaine. The crystal structure of O-benzoyltropine hydrochloride, determined by X-ray analysis, showed that the cation does not have the over-all shape and dimensions characteristic of potent anticholinergic agents. The 3/8- and 3a-propananilido-tropanes have been synthesized and were studied by g.l.c. and n.m.r. analysis, The 3/S-isomers exist in the chair form, whereas the 3a-isomers assume a flattened chair conformation, in agreement with a previous study. ... 

After determining cocaine s structure, chemists could ask, "How is the structure of cocaine related to its anesthetic effects Can the anesthetic effects be separated from the habituation effect " If these questions could be answered, it might be possible to prepare synthetic drugs with the structural features essential for the anesthetic activity but without those giving rise to the undesirable effects. Chem -ists focused on three structural features of cocaine its benzoic ester, its basic nitrogen atom, and something of its carbon skeleton. This search resulted in 1905 in the synthesis of procaine, which almost immediately replaced cocaine in dentistry and surgery. Lidocaine was introduced in 1948 and today is one of the most widely used local anesthetics. More recently, other members of the "caine" family of local anesthetics have been introduced (e.g., etidocaine). All of these local anesthetics are administered as their water-soluble hydrochloride salts. 

As with most complexation and drug solubility situations, pH b a critical variable. Cocaine base b not soluble in water, and if the drug b in thb form rather than a soluble salt, no reaction occurs. Acid b needed to ensure that the cocaine b in the water-soluble ionic form to allow for the formation of a complex. The color b the result of an ion-pair compound formed from the cationic cocaine and the anionic cobalt complex. As with all amine bases, such as ammonia, the base becomes protonated in acidic solution. The pKg of the base determines the ratio of the protonated, ionized form to the neutral form. It is possible to add too much HQ, because cobalt forms a water-soluble pink complex with chloride [CoCy . The pH can also influence the type of complex and ion pair formed. Under acidic conditions, the ion pair favored b [Co(cocaine)2l(SCN)2 (which b pinkbh and soluble in water), while in the neutral-to-basic ranges, the ion pair b assigned the structure [cocaine-H ]2 [Co(SCN)4] (which b a blue solid and soluble in chloroform). The important points of the cobalt thiocyanate reaction with cocaine are summarized in Figures 7.24r-7.26. 

The chemical structure of A -tetrahydrocannabinol, determined by Gaoni and Mechoulam in 1964, is illustrated in Figure 6.3. Unlike many other biologically active chemicals of plant origin, A -tetrahydrocannabinol is a highly hydrophobic molecule, a property that has hindered the progress on its mode of action for nearly three decades. Indeed, not only was A -tetrahydrocannabinol more difficult to handle experimentally than such hydrophylic alkaloids as cocaine or morphine, but also its preference for lipid... 

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