Benzofuro[2,3-c]pyridin-6-ols: synthesis, affinity for opioid-receptor subtypes, and antinociceptive activity

Abstract

A general synthetic approach to a novel series of cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols is described together with their receptor-binding profile on opioid-receptor subtypes (mu, kappa, delta). In addition, their in vivo antinociceptive activity was assessed. A number of the analogues synthesized showed potent affinity for opioid receptors and have potent antinociceptive activity in a mouse phenylquinone abdominal stretching model. In addition, the SAR for nitrogen substitution in the above series is explored with respect to the overall opioid receptor subtype binding profile. In general it was found that substituents which enhanced mu and kappa binding affinity in the benzomorphan series had a similar effect in the benzofuropyridine series described in this manuscript. An overlap hypothesis topologically connecting the benzomorphan nucleus to the cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine nucleus is also presented.

Probes for narcotic receptor mediated phenomena. 47.1 Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

“…In the C4a-alkyl, N -methyl series 2f–j , the affinity for μ receptors was optimal when C4a was ethyl, in 2g , as found by Hutchison et al, 2 and the compound with the highest affinity at δ-receptors was determined to be 2j , with a C4a-pentyl group ( K i = 33 nM, Table 1). The affinity increased with chain-length, from propyl ( 2h , K i = 479 nM) to butyl ( 2i , K i = 207 nM) to pentyl ( 2j , K i = 33 nM).…”

“…2 Benzofuro[2,3- c ]pyridinols are partial structures of oxide-bridged phenylmorphans. Although they appear to be structurally similar to the d-series of the oxide-bridged phenylmorphans, 3–5 the presence of a truncated C4a group gives the benzofuropyridinols a flexibility that is lacking in the rigid oxide-bridged phenylmorphans.…”

“…This flexibility may enable them to assume a conformation that is closer to morphine than the oxide-bridged phenylmorphans are able to assume, and their opioid affinity and activity may be correlated with their ability to attain this conformation. 6 Hutchison et al 2 found that the C4a-ethyl-substituted N -phenethyl- and N -cyclopropylmethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols ( 1a and 1b , respectively), had high affinity for μ-opioid receptors ( K i = 0.9 and 4 nM, respectively) and were potent antinociceptives. While Hutchison’s work focused on the opioid affinity based on N-variations on the piperidine ring, we thought it would be of interest to explore the effect of C4a group as well as the importance of the ethyl group at this position on opioid receptor affinity.…”

Probes for narcotic receptor mediated phenomena 49. N-substituted rac-cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

“…From our work[1-3] and that of Hutchison et al[4] it has been shown that cis -1,2,3,4,4a,9ahexahydrobenzofuro[2,3- c ]pyridin-6-ols ( 1 , Fig. 1), when suitably substituted on the tertiary nitrogen and the C4a-position, have high or moderate affinity for either μ-, δ- and κ-opioid receptors, and sometimes at a combination of these receptors [4].…”

“…1), when suitably substituted on the tertiary nitrogen and the C4a-position, have high or moderate affinity for either μ-, δ- and κ-opioid receptors, and sometimes at a combination of these receptors [4]. In principle, then, substituent modifications at these positions could lead to compounds that interact with a desirable combination of $\tilde{\mu }$ and δ-opioid receptor affinity.…”