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This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

This study describes the synthesis of a series of novel substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines, and discusses their structure-activity relationships (SARs) using binding affinity for opioid receptors and antinociceptive potency as the indices of biological activity. The introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated a compound, 40, which is 2 times more potent than the previously disclosed unsubstituted analogue 39 in mouse models of antinociception. A QSAR analysis of the 5-substitution clearly demonstrates that antinociceptive activity is inversely associated with the lipophilicity of the substituents. The substituted compounds described herein are less selective for the kappa opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for kappa opioid receptors (Ki kappa = 0.09 nM) and a Ki mu/Ki kappa ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the mu opioid receptor. On the other hand, the correlation between binding affinity to kappa opioid receptor and antinociceptive activity was statistically significant.

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.

This paper describes the synthesis and structure-activity relationships as kappa opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives. The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60 degrees, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and kappa affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl )piperidine hydrochloride and (2S)-1-[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmet hyl) piperidine hydrochloride are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (Ki kappa 0.24 and 0.57 nM, respectively) kappa ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard kappa ligand U-50488.