Elements of the<unk>  structure have been used to create completely synthetic drugs such as the<unk> n family (levorphanol, dextromethorphan and others) and other groups that have many members with<unk> -like qualities. The<unk> dification of<unk>  and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics,<unk> scle relaxants, local anaesthetics, general anaesthetics, and others.<unk> -derived agonist–antagonist drugs have also been developed. Structure description Chemical structure of<unk> . The benzylisoquinoline backbone is shown in green.<unk>  structure showing its standard ring lettering and carbon numbering system. Same structure, but in a three-dimensional perspective.<unk>  is a benzylisoquinoline alkaloid with two additional ring closures. As Jack DeRuiter of the Department of Drug Discovery and Development (formerly, Pharmacal Sciences), Harrison School of Pharmacy, Auburn University stated in his Fall 2000 course notes for that earlier department's "Principles of Drug Action 2" course, "Examination of the<unk> <unk> lecule reveals the following structural features important to its pharmacological profile... # A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturated cyclohexane rings (B and C), a piperidine ring (D) and a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system. This ring system has little conformational flexibility... # Two hydroxyl functional groups: a C3-phenolic hydroxyl group (pKa 9.9) and a C6-allylic hydroxyl group, # An ether linkage between C4 and C5, # Unsaturation between C7 and C8, # A basic, tertiary-amine function at position 17, and # Five centers of chirality (C5, C6, C9, C13 and C14) with<unk>  exhibiting a high degree of stereoselectivity of analgesic action."<unk>  and<unk> st of its derivatives do not exhibit optical isomerism, although some<unk> re distant relatives like the<unk> n series (levorphanol, dextorphan and the racemic parent chemical racemorphan) do, and as noted above stereoselectivity in vivo is an important issue. Uses and derivatives<unk> st of the licit<unk>  produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone).<unk> st semi-synthetic opioids, both of the<unk>  and codeine subgroups, are created by<unk> difying one or<unk> re of the following: * Halogenating or making other<unk> difications at positions 1 or 2 on the<unk>  carbon skeleton. * The methyl group that makes<unk>  into codeine can be removed or added back, or replaced with another functional group like ethyl and others to make codeine analogues of<unk> -derived drugs and vice versa. Codeine analogues of<unk> -based drugs often serve as prodrugs of the stronger drug, as in codeine and<unk> , hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc. * Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or<unk> difying functional groups to these positions; saturating, reducing, eliminating, or otherwise<unk> difying the 7–8 bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7–8 bond to single from double changes codeine into oxycodone. * Attachment, removal or<unk> dification of functional groups to positions 3 or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of<unk> ving the methyl functional group from position 3 to 6, codeine becomes heterocodeine, which is 72 times stronger, and therefore six times stronger than<unk>  * Attachment of functional groups or other<unk> dification at position 14 (oxymorphone, oxycodone, naloxone) *<unk> difications at positions 2, 4, 5 or 17, usually along with other changes to the<unk> lecule elsewhere on the<unk>  skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of<unk>  and codeine. Many<unk>  derivatives can also be manufactured using thebaine or codeine as a starting material. Replacement of the N-methyl group of<unk>  with an N-phenylethyl group results in a product that is 18 times<unk> re powerful than<unk>  in its opiate agonist potency. Combining this<unk> dification with the replacement of the 6-hydroxyl with a 6-methylene group produces a compound some 1,443 times<unk> re potent than<unk> , stronger than the Bentley compounds such as etorphine (M99, the Immobilon tranquilliser dart) by some measures. Closely related to<unk>  are the opioids<unk> -N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use; and pseudomorphine, an alkaloid that exists in opium, form as degradation products of<unk> . As a result of the extensive study and use of this<unk> lecule,<unk> re than 250<unk>  derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25% the analgesic strength of codeine (or slightly<unk> re than 2% of the strength of<unk>  to several thousand times the strength of<unk> , to powerful opioid antagonists, including naloxone (Narcan), naltrexone (Trexan), diprenorphine (M5050, the reversing agent for the Immobilon dart) and nalorphine (Nalline). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from<unk> . The receptor-activation profile of the semi-synthetic<unk>  derivatives varies widely and some, like apomorphine are devoid of narcotic effects. Salts Both<unk>  and its hydrated form are sparingly soluble in water. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times<unk> re water-soluble than their parent<unk> lecule. Whereas the pH of a saturated<unk>  hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the<unk>  salts are mixed with small amounts of NaOH to make them suitable for injection. A number of salts of<unk>  are used, with the<unk> st common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below.<unk>  diacetate (heroin) is not a salt, but rather a further derivative, see above.<unk>  meconate is a major form of the alkaloid in the poppy, as is<unk>  pectinate, nitrate, sulfate, and some others. Like codeine, dihydrocodeine and other (especially older) opiates,<unk>  has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the NSAID;<unk> ltiple barbiturate salts of<unk>  were also used in the past, as was/is<unk>  valerate, the salt of the acid being the active principle of valerian. Calcium<unk> rphenate is the intermediate in various latex and poppy-straw methods of<unk>  production,<unk> re rarely sodium<unk> rphenate takes its place.<unk>  ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation. The salts listed by the United States Drug Enforcement Administration for reporting purposes, in addition to a few others, are as follows: Select salts of<unk>  with their Controlled Substances Act (CSA) schedule, Administrative Controlled Substances Code Number (ACSCN), and free base conversion ratio. Salt or drug CSA schedule ACSCN Free base conversion ratio<unk>  (base) II 9300 1<unk>  citrate II 9300 0.81<unk>  bitartrate II 9300 0.66<unk>  stearate II 9300 0.51<unk>  phthalate II 9300 0.89<unk>  hydrobromide II 9300 0.78<unk>  hydrobromide (2 H2O) II 9300 0.71<unk>  hydrochloride II 9300 0.89<unk>  hydrochloride (3 H2O) II 9300 0.76<unk>  acetate II 9300 0.71<unk>  hydriodide (2 H2O) II 9300 0.64<unk>  lactate II 9300 0.76<unk> <unk> nohydrate II 9300 0.94<unk>  meconate (5 H2O) II 9300 0.66<unk> <unk> cate II 9300 0.57<unk>  nitrate II 9300 0.82<unk>  phosphate ( H2O) II 9300 0.73<unk>  phosphate (7 H2O) II 9300 0.73<unk>  salicylate II 9300<unk>  pectinate II 9300 0.778<unk>  phenylpropionate II 9300 0.65<unk>  methyliodide II 9300 0.67<unk>  isobutyrate II 9300 0.76<unk>  hypophosphite II 9300 0.81<unk>  sulfate (5 H2O) II 9300 0.75<unk>  tannate II 9300<unk>  tartrate (3 H2O) II 9300 0.74<unk>  valerate II 9300 0.74<unk>  diethylbarbiturate II 9300 0.619<unk>  cyclopentylallylbarbiturate II 9300 0.561<unk>  diacetate I 9200 0.74<unk>  methylbromide I 9305 0.75<unk>  methylsulfonate I 9306 0.75<unk> -N-oxide I 9307 1<unk> -N-oxide quinate I 9307 0.60<unk>  dinicotinate HCl (Nicomorphine) II 9312 0.931
Morphine
Codeine
Nalorphine
Methadone
Isomethadone
Normethadone
Butorphanol
Fentanyl