Antipodal .alpha.-N-(Methyl through Decyl)-N-normetazocines (5,9.alpha.-Dimethyl-2'-hydroxy-6,7-benzomorphans): In vitro and In vivo Properties

Abstract

The enantiomeric (-)- and (+)-N-(methyl through decyl) normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans) were synthesized and their in vitro and in vivo activities determined. Increasingly bulky enantiomeric N-alkyl homologs were prepared until their interaction with the sigma 1 receptor decreased and their insolubility became a hindrance to their evaluation in vivo and/or in vitro. The (-)-methyl, -pentyl, -hexyl, and -heptyl homologs were essentially as potent as, or more potent than, morphine in the tail-flick, phenylquinone, and hot-plate assays for antinociceptive activity; the (-)-propyl homolog had narcotic antagonist activity between that of nalorphine and naloxone in the tail-flick vs morphine assay, and it also displayed antagonist properties in the single-dose suppression assay in the rhesus monkey. The antinociceptively potent (-)-heptyl homolog did not substitute for morphine in monkeys but did show morphine-like properties in a primary physical-dependence study in continuously infused rats. All five potent compounds showed high affinity for the mu opioid receptor from both rat and monkey preparations and the kappa opioid receptor (< 0.05 microM), and all except the (-)-methyl homolog interacted reasonably well at the delta receptor (K(i) < 0.1 microM). The (-)-propyl compound was equipotent (K(i) 1.5-2.0 nM) at mu and kappa receptors. The pattern of interaction of the (-)-enantiomeric homologs with mu receptors from rat and monkey preparations was similar, but not identical. The enantioselectivity of the homologs for mu receptors was greater in the rat than in the monkey preparation for all but the N-H and butyl compounds, and the enantioselectivity of the lower homologs (methyl through butyl) for the mu (monkey) receptor was greater than for the kappa or delta receptors. However, bulkier homologs (hexyl through decyl) displayed higher enantioselectivity at kappa or delta receptors than at the mu (monkey) receptor. The (+)-butyl through (+)-octyl homologs were essentially equipotent with, or more potent than, (+)-pentazocine at the sigma receptor. Only the (+)-H and (+)-methyl homologs had high affinity (< 0.05 microM) at PCP binding sites.

Pharmacological studies with a nonpeptidic, delta-opioid (−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((−)-NIH 11082)

“…Previous studies in our laboratory with (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(methyl through decyl)-6,7-benzomorphans revealed a transition of activity (May et al,1994). Antinociceptive acitivy in the mouse went from agonist ((-)-methyl) to agonist antagonist ((-)-ethyl, (-)-propyl and (-)-butyl) and back to agonist ((-)-pentyl, (-)-hexyl, -(-)-heptyl, and (-)-octyl).…”

Sigma receptors [σRs]: biology in normal and diseased states

“…Opioids have subtle differences in binding to the µ, κ and σRs; however, σRs are a receptor class in their own right ( 297 , 298 ). Although σRs now have been classified as a separate group of receptors from the opioid receptors, the outcome of σR binding is not necessarily different from that when these receptors are bound to opiates ( Figure 5 ) ( 299 ), especially since interactions between κRs and σRs have been reported ( 278 , 300 ).

Figure 5.

…”

Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

“…This nucleus is a rigid scaffold able to support the phenolic ring and the basic nitrogen in a correct conformation mimicking the tyramine of opioid peptides [ 4 ]. A plethora of experimental evidence demonstrated the unpredictability of agonist and antagonist properties conferred by N -substituents on 6,7-benzomorphan ligands [ 5 , 6 , 7 , 8 , 9 ]. Thus, our approach consisted in the introduction at the basic nitrogen of the cis -(−)- N -normetazocine nucleus of different functional groups with the aim to explore their influence on the mu, delta and kappa opioid receptor (MOR, DOR and KOR) affinity, selectivity and activity in the resulting compounds.…”