Optical isomers of miscellaneous strong analgetics

Abstract

parallels very well with the lipophilic character of the four analgeticis. Of special interest is the good agreement of the slopes of eq 9 and 11. This reflects a close parallelism between log (CbrainlCplasma) and log ( C l v e n t r l Ci,.) . This is additional support for the earlier findings that log ( C l r e n t r / C i v ) is a measure of the different capability of the analgetics to penetrate the blood-brain barrier.

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

“…NIH8508, although it was the least efficacious of the partial agonists, had about the same intrinsic efficacy as pentazocine. The low efficacy of NIH8508 is consistent with reports of its being able to precipitate an abstinence syndrome (May and Takeda, 1970). Its stereoisomer NIH8509 had about the same level of efficacy as pentazocine and buprenorphine and the intrinsic efficacy of a fully efficacious agonist.…”

“…Table I, that these compounds were -selective. Consistent with studies demonstrating agonist action in mice (May and Takeda, 1970), NIH8508 and NIH8509 stimulated [ 35 S]-GTP-␥-S binding with ED 50 values of 203 nM and 188 nM, respectively. The binding affinity of NIH8508 and NIH8509 for the cloned rat receptor assayed under [ 35 S]-GTP-␥-S conditions with [ 125 I]IOXY was much lower than when assayed with [ 3 H]DAMGO under standard assay conditions, reflecting the "sodium shift" seen with agonist type drugs (Pert and Snyder, 1974).…”

“…Its stereoisomer NIH8509 had about the same level of efficacy as pentazocine and buprenorphine and the intrinsic efficacy of a fully efficacious agonist. Unlike pentazocine, which can precipitate an abstinence syndrome (Beaver, 1966), NIH8509 does not (May and Takeda, 1970). It is interesting to speculate that the high intrinsic efficacy of NIH8509 explains this interesting observation.…”

“…NIH8508 is an analgetic with morphine-like potency which has no physical dependence capacity in monkeys (single-dose experiments), but will precipitate abstinence symptom in monkeys stabilized and dependent on morphine. In contrast, NIH8509 does not produce an abstinence syndrome (Rogers and May, 1974;May and Takeda, 1970).…”

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

“…The nitro group was reduced and the resulting aniline derivative was converted into a free phenol via hydrolysis of the corresponding diazonium salt assisted by copper salts, furnishing the para-e N-methyl oxide-bridged phenylmorphan 2. 3 Quaternary salt 12 was prepared in larger quantities and used as a convenient starting material for the synthesis of the N-phenethyl derivatives in the para-e oxide-bridged series (Scheme 1), as was (1R*,4aR*,9aS*)-2-methyl-6-nitro-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro [2,3-c]pyridine (15) for the para-f oxide-bridged series (Scheme 2).…”