ABSTRACT
The 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor.
Subject(s)
Analgesics, Opioid/chemistry , Carboxylic Acids/chemistry , Ethylketocyclazocine/analogs & derivatives , Pyridines/chemistry , Receptors, Opioid, kappa/agonists , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/chemistry , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology , Analgesics, Opioid/pharmacology , Animals , Brain/metabolism , Carboxylic Acids/pharmacology , Ethylketocyclazocine/chemistry , Ethylketocyclazocine/pharmacology , Models, Molecular , Molecular Structure , Pyridines/pharmacology , Quantitative Structure-Activity Relationship , RatsABSTRACT
Local anaesthetics and opioid drugs function synergistically to provide analgesia. In the present study, the nature of this synergy has been investigated using in vitro radioligand binding to determine whether the local anaesthetics bupivacaine and tetracaine modulate the binding of two kappa-opioid receptor ligands, [3H]U-69593 (5-alpha,7-alpha,8-beta-(-)-N-methyl-N[7-(1-pyrrolodinyl)-1-oxa spiro(4,5)dec-8-yl]-benzene acetamide) and [3H](-)-EKC (ethylketocyclazocine). [3H]U-69593 bound with a KD of 0.88 nM and a Bmax of 2.39 +/- 0.22 fmol/mg wet weight in guinea pig cerebellar membranes. The binding was inhibited by bremazocine and morphine with Hill slopes near unity and pI50 values of 9.96 and 6.84-6.86, respectively. [3H]U-69593 binding was inhibited by Gpp(NH)p (5'-guanylyl imidodiphosphate) and NaCl, consistent with an agonist action of the compound. The binding characteristics of the ligand were not changed by bupivacaine or tetracaine. [3H](-)-EKC bound with KD values of 0.55 and 0.97 nM and Bmax values of 4.22 and 0.99 fmol/mg wet weight in guinea pig cerebellar membranes and rat spinal cords, respectively. In the rat spinal cord, [3H](-)-EKC appeared to act as an agonist/antagonist, since the presence of Gpp(NH)p and NaCl only produced a small (21%) reduction in binding, but reduced the pI50 for the residual binding to inhibition by morphine from 6.33-6.39 to 5.95. As with [3H]U-69593, the binding characteristics of [3H](-)-EKC were not affected by bupivacaine or tetracaine. These studies demonstrate that effects of kappa-opioid receptor recognition site conformation are unlikely to explain the clinically observed synergy between local anaesthetics and opioids.
Subject(s)
Anesthetics, Local/pharmacology , Benzeneacetamides , Receptors, Opioid, kappa/drug effects , Animals , Binding Sites , Bupivacaine/pharmacology , Drug Synergism , Ethylketocyclazocine/chemistry , Guinea Pigs , Morphine/pharmacology , Pyrrolidines/antagonists & inhibitors , Pyrrolidines/chemistry , Rats , Receptors, Opioid, kappa/chemistry , Tetracaine/pharmacologyABSTRACT
The X-ray molecular structures of the narcotic analgesics alpha-(-)-2-cis-3-chlorallyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorp han (1) and alpha-(+-)-2-cyclopropylmethyl-2'-hydroxy-5-ethyl-9-methyl-8-oxo-6,7- benzomorphan (ethylketazocine, 2) were determined. The structures and conformations in the crystal were compared and discussed with respect to that of alpha-(+-)-2-cyclopropylmethyl-2'-hydroxy-5,9-dimethyl-8- oxo-6,7-benzomorfan (ketazocine, 3) and those of 15 analogous compounds of the 2'-hydroxy-6,7-benzomorphan series whose structures were previously determined by X-ray analysis. Molecular modeling routines for 1, 2, and 3 produced configurations (N-equatorial) and conformations (distorted chair) of the piperidine ring that were in agreement with those found in the solids. Theoretical studies of the conformations and the rotational energetics of 1, 2, and 3 as cationic species were performed by both the force field (MM2) and the semiquantitative (AM1) methods. The latter method predicted three low energy conformations about N--C(12) and C(12)--C(13) bonds, one of these being more significantly populated (60-68%). The AM1 results were not reproduced by the MM2 method, which predicted four low energy conformations. An interesting common feature of 1, 2, and 3 that was noted with both methods was the restricted interconversion route from the conformational state to another through rotations about the C(12)--C(13) bond. The conformational results were discussed in terms of a working hypothesis for regulation of relative mu and kappa analgesic activities of benzomorphans.
