J Pharm Pharmacol 1980 Sep;32(9):635-42

Analgesic and other pharmacological activities of a new

narcotic antagonist analgesic (-)-1-(3-methyl-2-butenyl)4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazine and
its enantiomorph in experimental animals.
Nakamura H, Ishii D, Yokoyama Y, Motoyoshi S, Natsuka K, Shimizu M
Of 1-chclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (I) and its 1-(3-methyl-2-butenyl)
derivative (II), the S(+)-isomers were analgesically more active than either their +(-)-isomers or their
racemates, having 15 to 44 times the potency of morphine in mice and rats. R(-)-I had comparable
analgesic activity to morphine R(-)-II to pentazocine in mice, rats and dogs and they were nearly equipotent
with pentazocine in reversing some actions of morphine. The S(+)-isomers and racemates lacked this
action. R(-)-II required about 10 times more naloxone to reverse its analgesic activity than was needed to
antagonise the S(+)-isomers, morphine and pentazocine. The S(+)-isomers and racemates produce a typical
Straub tail reaction and increased spontaneous locomotor activity in mice, but the R(-)-isomers did not. R()-II had no significant physical dependence liability in mice, rats and monkeys. From these results, it is
suggested that the compounds show an uncommon steroselectivity in comparison with morphine and its
surrogates, and that R(-)-II is worth investigating further as a narcotic antagonist analgesic.
PMID: 6107365, UI: 81049058

Jpn J Pharmacol 1978 Jun;28(3):505-6

Analgesic activity and opiate receptor binding of 1cyclohexyl-4-(1,2-diphenylethyl)piperazine.

Fujimura H, Tsurumi K, Nozaki M, Hori M, Imai E
PMID: 212626, UI: 79030307

J Med Chem 1987 Oct;30(10):1779-87

Synthesis and structure-activity relationships of 1substituted 4-(1,2-diphenylethyl)piperazine derivatives

having narcotic agonist and antagonist activity.
Natsuka K, Nakamura H, Nishikawa Y, Negoro T, Uno H, Nishimura H
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives
(3-18) were synthesized, and their analgesic and other pharmacological activities and structure-activity
relationships were investigated. The S-(+) enantiomers of 2a, 5, 7, 9, 10, and 15-18 had a stronger analgesic
activity than their R-(-) enantiomers; analgesic activity of the strongest one [(S)-(+)-10] was 105 times as
potent as that of morphine. The S-(+) enantiomers of these compounds had the opposite configuration to
that of morphine with respect to its (C-9) asymmetric center but the same configuration to that of the
tyrosine residue of Met5-enkephalin. The R-(-) enantiomers of 16 and 18 showed narcotic antagonist
activity, but the S-(+) enantiomers did not. (R)-(-)-18 had analgesic and narcotic antagonist activities

comparable to pentazocine but showed no significant physical dependence liability. From these results, it is
suggested that these compounds show an uncommon enantioselectivity in comparison with morphine and
its surrogates, and belong to a new series of compounds having a potent analgesic activity.
PMID: 3656354, UI: 88011118

J Med Chem 1975 Dec;18(12):1240-4

Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine

derivatives and their analgesic activities. 1.
Natsuka K, Nakamura H, Uno H, Umemoto S
The preparation and analgesic activities of a series of the entitled compounds (5-22) and the optical isomers
of the 1-cyclohexyl derivative 5 are described. Reactions of N,N-bis(2-chloroethyl)-1,2diphenylethylamine (3) with ammonia and primary amines gave N-(1,2-diphenylethyl)piperazine (4) and
N1-substituted derivatives (5-20, 22), respectively. The alkylation of 4 afforded 12-21. Compounds 5-18
and 22 were also obtained by the reactions of 1,2-diphenylethylamine (23) and N-substituted 2,2'dichlorodiethylamine. Racemate 5 was resolved with (+)- or (-)-2'-nitrotartranilic acid into its optical
isomers [(+)-5 and (-)-5], and the absolute configuration of (+)-5 was determined to be S configuration by
the synthesis and optical rotatory dispersion measurements. The most active members in this series of
compounds were 5-7, which were approximately as potent as (-)-morphine. In the case of 5, the more
potent enantiomer (S)-(+)-5 has the opposite configuration to that of (-)-N,N-dimethyl-1,2diphenylethylamine (Spa) or (-)-morphine with respect to the (C-9) asymmetric center and belongs to a new
series of compounds having potent analgesic activity.
PMID: 1195277, UI: 76071840
Arch Int Pharmacodyn Ther 1976 May;221(1):105-21

Comparative study of 1-cyclohexyl-4-(1,2diphenylethyl)-piperazine and its enantiomorphs on

analgesic and othe pharmacological activities in
experimental animals.
Nakamura H, Shimizu M
The analgesic activity of (+/-)-1-cycylohexyl-4-(1,2-diphenylethyl)-piperazine (MT-45) was comparable to
that of morphine. The activity of the S(+)-isomer was 1.14 to 1.97 times in mice and 1.00 and 1.23 times in
rats as potent as MT-45, and 18.3 to 61.6 times as potent as the R(--)isomer, which was approximately
comparable to that of Spa. The hyperglycemic and miotic activities of MT-45 and its S(+)-isomer in rabbits
were negligible or very low, though they showed potent morphine-like activites. On the other hand, the R(-)-isomer showed no or very weak effects on those, while Spa showed definite effects. These results suggest
that the modes of action of MT-45 and its enantiomorphs are partly different from those of morphine and
Spa, and it may be concluded that MT-45 belongs to a new series of compounds having a potent analgesic
activity.
PMID: 962421, UI: 76276760

Life Sci 1983;33 Suppl 1:431-4

(1,2-Diphenylethyl) piperazines as potent opiate-like

analgesics; the unusual relationships between
stereoselectivity and affinity to opioid receptor.
Nozaki M, Niwa M, Imai E, Hori M, Fujimura H
A series of novel diphenylethylpiperazines were synthesized, and analgesic activities and opioid receptor
interactions were evaluated. Analgesic activity of S(+) enantiomer of 1-cyclohexyl analogues (I-C6) was as
potent as morphine. This compound showed narcotic properties. Racemate of I-C6 demonstrated the most
potent analgesic activities among the enantiomorphic pairs. The R(-) isomer and (-) spa, NN-dimethyl-1, 2diphenylethylamine, had mu-agonist like character. The S(+) isomer possessed high affinity for all types of
the receptor, especially favorable for delta and kappa, in the different manner from opiate-like analgesics. It
is conceivable that opioid receptor has various subsites, and this S(+) enantiomer alter the conformation of
the receptor.
PMID: 6319898, UI: 84116623
Chem Pharm Bull (Tokyo) 1999 Dec;47(12):1790-3

Roles of two basic nitrogen atoms in 1-substituted 4(1,2-diphenylethyl)piperazine derivatives in production

of opioid agonist and antagonist activities.
Natsuka K, Nishikawa Y, Nakamura H
Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
[Medline record in process]
To ascertain roles of the two basic nitrogen atoms in 1-substituted 4-[2,(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives (1) in the expression of opioid agonist and antagonist activities, a methine group
(CH) was isosterically substituted for nitrogen atom at the 1-position (N-1) in compound 1 to obtain 4substituted 1-[2-(3-hydroxyphenyl)-1-phenylethyl]piperidine derivatives (2). Their analgesic action and
ability to produce physical dependence (jump-producing activity) as the mu-opioid receptor specific in vivo
actions, and narcotic antagonist action in mice were compared with those of compound 1. Results of this
study showed that, in cases of the racemate and the (S)-(+) enantiomer, opioid agonist activities (analgesic
and jump-producing activities) were not greatly affected by the methine-substitution for N-1 in compound
1, but that the narcotic antagonist activity of the (R)-(-) enatiomer was abolished by this substitution. It thus
appears that N-1 in compound 1 contributes to the expression of narcotic antagonist activity, whereas the
nitrogen atom at the 4-position corresponds to the tyramine moiety necessary for the expression of muopioid agonist activity.
PMID: 10748722, UI: 20212210