tan-67 and Pain

We designed the nonpeptidic highly selective delta opioid receptor agonist on the basis of message address concept and the accessory site theory and synthesized (+/-) TAN-67. In spite of highly potent agonistic activity in in vitro assay, (+/-) TAN-67 (racemate) afforded a weak antinociceptive effect in the mouse tail-flick test. This result led us to separate (+/-) TAN-67 to optical pure compounds, (+) and (-) TAN-67. An i.t.-treatment with (-) TAN-67 produced profound antinociceptive effects through specifically acting on delta1 receptors. Unlike (-) TAN-67, i.t.-administered (+) TAN-67 displayed dose-related nociceptive behaviors such as scratching, biting and licking. The effect of (+) TAN-67 was blocked by i.t.-treatment with NTI (delta receptor antagonist) and (-) TAN-67 (delta1 receptor agonist), but not by morphine (mu receptor agonist). The mechanisms involved in spinal pain modulation induced by (+) and (-) TAN-67 were also described.

Topics: Analgesics; Animals; Binding Sites; Dose-Response Relationship, Drug; Drug Design; Guinea Pigs; Ligands; Mice; Models, Biological; Nociceptors; Pain; Quinolines; Receptors, Opioid, delta; Stereoisomerism

The activation of the delta-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal dopamine efflux. (+/-)-TAN-67 (2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octahydro-quinolino[2,3,3,-g]isoquinoline) is a centrally acting non-peptidic delta opioid receptor agent which has recently become available. Interestingly, the (+) enantiomer of TAN-67 induces hyperalgesia in contrast to the (-) enantiomer of TAN-67 that produces profound antinociceptive effects in mice; the latter effects are mediated through delta-1 receptor stimulation. Using the microdialysis technique, the ability of the enantiomers of TAN-67 to alter the release of accumbal dopamine in vivo was analyzed. Like the 25-min infusion of the selective delta-1 opioid receptor agonist (D-[Pen2,5]-enkephalin) DPDPE (50 nM) and the delta-2 opioid receptor agonist deltorphin II (50 nM), the 25-min infusion of both (-)-TAN-67 (25 and 50 nM) and (+)-TAN-67 (25 and 50 nM) into the nucleus accumbens produced a similar transient dose-dependent increase in the accumbal extracellular dopamine level. Naloxone (1 mg/kg i.p., given 25 min prior to the drugs), namely a treatment that is known to inhibit the increase of dopamine induced by DPDPE and deltorphin II, did not affect the transient increase in the accumbal dopamine level produced by infusion of the enantiomers of TAN-67. The DPDPE and deltorphin II-induced increase in accumbal dopamine level, but not that of (-)-TAN-67 and (+)-TAN-67, was eliminated by subsequently perfused tetrodotoxin (2 microM) into the nucleus accumbens. The increase in accumbal dopamine level produced by an infusion of (-)-TAN-67 and (+)-TAN-67 was not altered by a Ca2+-free Ringer's solution. The (-)-TAN-67 and (+)-TAN-67-induced accumbal dopamine efflux was strongly prevented by reserpine (5 mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of the enantiomers of TAN-67 on the accumbal dopamine were nullified by combined treatment with reserpine and alpha-methyl-para-tyrosine. The (-)-TAN-induced dopamine efflux was significantly reduced by the N-methyl-D-aspartate (NMDA) receptor antagonists ifenprodil (20 mg/kg i.p., 20 min before) and MK-801 (0.5 mg/kg i.p., 20 min before), respectively. The effects of (-)-TAN-67 on the dopamine efflux were also inhibited by the free radical scavenger N-2-mercaptopropionyl glycine (100 mg/kg i.p., 20 min before). These re

Topics: Adrenergic Uptake Inhibitors; alpha-Methyltyrosine; Animals; Dopamine; Enkephalin, D-Penicillamine (2,5)-; Enzyme Inhibitors; Extracellular Space; Free Radicals; Glutamic Acid; Male; Microdialysis; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Oligopeptides; Pain; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, delta; Reserpine

The present study was designed to investigate the effect of a selective GABA(B) receptor agonist baclofen on the pain-like nociceptive behavior (scratching, biting and licking) induced by intrathecal (i.t.) injection of N-methyl-D-aspartate (NMDA) or (+)TAN-67, the enantiomorphs of 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha-octahydro-quinolino[2,3,3g]isoquinoline (TAN-67), in the mouse. NMDA (0.05-0.2 microg/mouse) given i.t. immediately caused nociception in a dose-dependent manner. The nociception was significantly antagonized by i.t. co-injection with dizocilipine (0.1-1.0 microg/mouse), a non-competitive NMDA receptor antagonist. I.t. co-injection with baclofen (37.5-150 ng/mouse) significantly reduced the NMDA-induced nociceptive behavior in a dose-dependent fashion. The inhibition produced by baclofen was completely reversed by a selective GABA(B) receptor antagonist 2-hydroxysaclofen (0.15 and 0.3 microg/mouse). An i.t. injection of (+)TAN-67 at doses of 3.75-15 microg/mouse elicited a long-lasting and a dose-related nociception. The nociceptive behavior induced by (+)TAN-67 given i.t. was markedly suppressed by i.t. co-injection with baclofen (3-30 ng/mouse), and the inhibitory effect of baclofen was prevented by i.t. injection of 2-hydroxysaclofen (1 and 3 microg/ mouse). In addition, the (+)TAN-67-induced nociception was also attenuated by i.t. co-injection with dizocilipine (0.1-1.0 microg/mouse). These results suggest that spinal GABA(B) receptors may be implicated in the expression of nociception elicited by i.t. injection of either NMDA or (+)TAN-67 in the mouse.

Topics: Analgesics; Animals; Baclofen; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA Agonists; Injections, Spinal; Male; Mice; N-Methylaspartate; Pain; Quinolines; Receptors, GABA-B; Spinal Cord

We designed highly selective non-peptide agonists for the delta-opioid receptor. On the basis of the "message-address" concept in this field and the accessory site hypothesis, a novel class of heterocycle-fused octahydroisoquinoline derivatives were synthesized. One of these compounds [(4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12, 12a -octahydropyrido[3,4-b]acridine, TAN-67 (2)] showed high selectivity for the delta-opioid receptor (Ki = 1.12 nM) in guinea-pig cerebrum with a 2070-fold lower affinity for the mu-opioid receptor and a 1600-fold lower affinity for the kappa-opioid receptor. TAN-67 was a potent delta-opioid receptor agonist with an IC50 value of 6.61 nM in the mouse vas deferens assay that was reversed by naltrindole (NTI) (Ke = 0.21). Moreover, TAN-67 was shown to have antinociceptive activity following subcutaneous administration in the mouse acetic acid abdominal constriction assay that was antagonized by NTI (delta 1- and delta 2-antagonist) and 7-benzylidinenaltrexone (delta 1-antagonist), but not by naltriben (delta 2-antagonist). This systemically applicable non-peptide agonist will be useful for elucidating the pharmacological properties of the delta-opioid receptor.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Brain; Drug Design; Guinea Pigs; In Vitro Techniques; Ligands; Male; Mice; Muscle, Smooth; Pain; Pain Measurement; Quinolines; Receptors, Opioid, delta

The effects of enantiomorphs of TAN-67 (2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino[2,3,3-g]isoquinoline), (-)TAN-67 and (+)TAN-67, given intrathecally (i.t.) on antinociceptive response with the tail-flick test were studied in male ICR mice. (-)TAN-67 at doses from 17.9 to 89.4 nmol given i.t. produced a dose- and time-dependent inhibition of the tail-flick response, whereas its enantiomer (+)TAN-67 even at smaller doses (1.8, 4.5 and 8.9 nmol) given i.t. decreased the latencies of the tail-flick response. In addition, (+)TAN-67 at higher doses (17.9-89.4 nmol) given i.t. produced scratching and biting pain-like responses. The antinociceptive response induced by i.t.-administered (-)TAN-67 was mediated by the stimulation of delta-1 but not by delta-2, mu or kappa opioid receptors, because the effect was blocked by the i.t. pretreatment with BNTX, but not by naltriben, [D-Phe-Cys-Tyr-[D-Try-Orn-Thr-Pen-Thr-NH2 or nor-binaltorphimine dihydrochloride. Pretreatment with (-)TAN-67 given i.t. 3 hr earlier attenuated the tail-flick inhibition induced by subsequent i.t. administration of (-)TAN-67 and by [D-Pen2,5]enkephalin (DPDPE). However, the tail-flick inhibition induced by [D-Ala2]deltorphin II, [D-Ala2,NMePhe4,Gly5-ol]enkephalin and U50,488H were not affected by (-)TAN-67 pretreatment. Conversely, pretreatment with DPDPE given i.t. 3 hr earlier attenuated the tail-flick inhibition induced by subsequent i.t. administration of (-)TAN-67 and by DPDPE. However, the tail-flick inhibition induced by [D-Ala2]deltorphin II was not affected by i.t. DPDPE pretreatment. It is concluded that (-)TAN-67 given i.t. produces delta-1 opioid receptor-mediated antinociception; on the other hand, its enantiomer (+)TAN-67 produces hyperalgesia. Present studies provide other evidence that delta-1 opioid receptors exist separated from delta-2 opioid receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Hyperalgesia; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Pain; Pain Measurement; Pyrrolidines; Quinolines; Reaction Time; Receptors, Opioid, delta; Spinal Cord