Ring constrained analogues of the orvinols: The furanomorphides

Structural Determinants of Opioid Activity in the Orvinols and Related Structures: Ethers of Orvinol and Isoorvinol

“…The proposed H-bonding interaction of the ethers with the κ-receptor would result in a conformation in which the benzyl group could access possible lipophilic sites in the spaces below C 8 or above C 7 . These sites which are occupied by cyclopentane rings in 9 and 10, respectively, are compatible with κ-agonist activity.…”

Structural Determinants of Efficacy for κ Opioid Receptors in the Orvinol Series: 7,7-Spiro Analogues of Buprenorphine

“…Surprisingly, in vitro pharmacological analysis of this series showed only small differences between the unsubstituted ( 2 , R = H) and disubstituted ( 2 , R = Me) compounds at any of the three receptors, each displaying κ agonist activity in the guinea pig ileum (GPI) and δ agonist activity in the mouse vas deferens (MVD) . Additionally our own studies with furanomorphides ( 3 ) have indicated that the presence or absence of methyl groups attached to C20 has no affect on their activity in vitro . Together, the above results lead us to conclude that the area below C7,C8 can accommodate alkyl groups but does not play a critical role in determining the pharmacological profile of the molecules.…”

“…studies with furanomorphides (3) have indicated that the presence or absence of methyl groups attached to C20 has no affect on their activity in vitro. 2 Together, the above results lead us to conclude that the area below C7,C8 can accommodate alkyl groups but does not play a critical role in determining the pharmacological profile of the molecules. Thus buprenorphine's unique profile and in particular its lack of κ agonist effects is unlikely to be associated with interactions at this site.…”

“…The standard tritiated ligands used for these assays were [ 3 H]DAMGO (μ), [ 3 H]U69,593 (κ), and [ 3 H]DPDPE-Cl (δ) . Each of the spiro analogues displayed nanomolar or subnanomolar affinities for all three receptor types, resulting in little selectivity, which is usual for orvinols and related series (Table ). ,, In general, the unsubstituted analogues ( 9a and 9b ) had marginally higher affinity for each receptor than the dimethyl analogues ( 10a and 10b ).…”

“…Buprenorphine's profile is believed to be derived in part from the location of the tert -butyl group attached to C20, although it is still not certain what conformation is adopted on binding to the receptor. In order to better define the role of this moiety we have prepared ring constrained analogues of buprenorphine in which the tert -butyl group is incorporated into a rigid ring system. , In the series of 7,8-fused analogues ( 2 ) 3 the ring is held in the region below C7,C8an area proposed by Rapoport to be critical for the expression of agonist activity in the orvinol and related series . Surprisingly, in vitro pharmacological analysis of this series showed only small differences between the unsubstituted ( 2 , R = H) and disubstituted ( 2 , R = Me) compounds at any of the three receptors, each displaying κ agonist activity in the guinea pig ileum (GPI) and δ agonist activity in the mouse vas deferens (MVD) .…”