morphinans and oripavine

The relative in vivo receptor affinities of three oripavine drugs given subcutaneously were determined at the mu, delta and kappa type of opiate binding sites in rat brain. The oripavines include the agonist etorphine, the antagonist diprenorphine and the mixed agonist-antagonist buprenorphine. With the use of mu, delta and kappa specific labeling conditions in brain homogenates immediately after sacrifice (ex vivo labeling), the method relies on the assay of those receptor sites that remain unbound in vivo. Because of the slow receptor binding kinetics of the oripavines, little or no dissociation of the in vivo ligand occurs during the ex vivo labeling period. All three drugs displayed lower affinity in vivo at the delta sites relative to mu sites, whereas the kappa affinities were highly variable. Etorphine displayed considerable mu selectivity, while burpenorphine's affinity at the mu and kappa sites was similar. The apparent in vivo binding affinities obtained from the ex vivo labeling approach are compatible with previous results where tracers were applied in vivo. The dramatic differences of the in vivo and in vitro opiate receptor binding properties of the oripavines demonstrate the need for in vivo receptor binding parameters in the analysis of the function of individual receptor types.

Topics: Animals; Brain; Buprenorphine; Diprenorphine; Etorphine; Kinetics; Male; Morphinans; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Thebaine

Buprenorphine (I), a member of the 6,14-endo-ethanotetrahydrooripavine series of analgesics, undergoes an acid-catalyzed rearrangement reaction when exposed to acid and heat. The product was shown by 1H-NMR and GC-MS to have undergone overall elimination of a molecule of methanol with concurrent formation of a tetrahydrofuran ring at C(6)-C(7) of I. Short-term stability studies across a wide range of pH and temperature conditions indicate that I is stable in aqueous solution at pH greater than 3 for 24 h at 36-38 degrees C. Under the more extreme conditions of the autoclave, significant loss of I occurred. Long-term stability studies (10 weeks) of I in aqueous solution (pH 1 and pH 5) at 0-4 degrees C and 26-28 degrees C indicate only minor conversion (4%) to the rearrangement product. Eight other 6,14-endo-ethanotetrahydrooripavine derivatives were subjected to extremes of acid (pH 0) and temperature (autoclave) to determine if similar rearrangement reactions occur. GC-MS indicated that hydrolysis products were produced whose spectra were consistent with the proposed rearrangement structures.

Topics: Analgesics; Buprenorphine; Catalysis; Drug Stability; Hydrogen-Ion Concentration; Hydrolysis; Morphinans; Thebaine

The 6-demethoxy analogue of thebaine has been easily prepared from codeine via isocodeine and its sulfenate ester. This diene, 7, readily undergoes reaction with vinyl ketones to afford Diels-Alder adducts of the 6,14-ethenomorphinan type. Further reactions afford the epimeric 19(R)- and 19(S)-butyl-6-demethoxy-7 alpha-orvinols (16). Pharmacological testing shows the R diastereomer to be highly analgesic and the s diastereomer to be a much less potent agonist, with similar potencies and relationships as found in the corresponding oripavine series. Thus, any hydrogen bonding between the 6-methoxyl group and the tertiary alcohol can be eliminated as contributory to either the activity of, or difference between the epimeric orvinols.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Morphinans; Rats; Reaction Time; Thebaine; Time Factors

Topics: Analgesics; Benzomorphans; Cyclohexanes; Humans; Kinetics; Morphinans; Morphine Derivatives; Piperidines; Propylamines; Thebaine