Similarities and differences between D-ALA2 MET5 enkephalin amide and morphine in the induction of tolerance to their effects on catalepsy and on dopamine metabolism in the rat brain.

Rats were made tolerant to morphine or to DALA, a synthetic analogue of met-enkephalin, by prolonged exposure to these compounds. Tolerance was assessed by evaluating the resistance of the treated rats to present catalepsy after an acute dose of the opiates. Both morphine and DALA induced tolerance and cross-tolerance to the cataleptic effect. Acute administration of morphine and DALA increased the concentration of DOPAC in striatum, limbic area and s.nigra of control rats. This increase was not present when morphine was given acutely to chronically morphine-treated rats, indicating that these animals were tolerant to this effect. Chronically morphine-treated rats given DALA presented partial tolerance to the biochemical effect of the peptide in limbic area and in s.nigra but not in striatum, indicating that only in certain areas was cross-tolerance produced by chronic morphine. When DALA was administered at different doses to chronically DALA treated rats, the peptide induced rise in DA catabolite was similar to that produced in control animals, so clearly there was no tolerance to this biochemical effect. In these animals cross tolerance to morphine's effect on DA metabolism was present in s.nigra but not in the other two areas, indicating that s.nigra is particularly sensitive to opiate-induced tolerance on DA metabolism.

Inhibition of inducible nitric oxide synthase in persistent pain.

The present study was undertaken to investigate the role of inducible nitric oxide synthase in a rat model of persistent pain. The effects of L-N6 (1-iminoethyl) lysine (L-NIL), a relatively potent and relatively selective inhibitor of inducible nitric oxide synthase, were investigated in carrageenan induced hyperalgesia L-NIL (0.1 microMole) injected intraplantar or intrathecal markedly enhanced carrageenan induced hyperalgesia. These effects were reversed during the third hour by co-administration of L-arginine (900 mg/kg i.p.) but not D-arginine. Methylene blue (MB), a soluble guanylate cyclase inhibitor, administered intrathecally (0.1 microg) had no effect on L-NIL potentiation of carrageenan hyperalgesia but abolished antinociception induced by L-arginine. Obtained results suggest that nitric oxide derived from inducible nitric oxide synthase play an inhibitory role in carrageenan produced hyperalgesia in rat.

Spinal co-administration of peptide substance P antagonist increases antinociceptive effect of the opioid peptide biphalin.

Intrathecal injection of 0.25 micrograms of undecapeptide substance P antagonist (SPA) produced transient antinociception with a peak effect at 5 min. Increasing the SPA dose resulted in neurotoxicity. Intrathecal injection of the opioid peptide biphalin (BIP) produced antinociception for over 3 hrs without neurotoxicity. Co-administration of SPA (at subtoxic doses) increased BIP's antinociceptive effect. Naltrexone reversed analgesia due to BIP alone as well as after BIP+SPA.

Bifunctional pharmacophores. Biological activities of the peptide analog containing both casomorphine-like and substance P antagonist-like active elements.

SP-antagonistic properties of a newly synthesized peptide Tyr-Pro-D-Phe-Phe-D-Phe-D-Trp-MetNH2 (AWL-60) were investigated both in vitro and in vivo. In vitro AWL-60 effectively antagonized the action of SP-agonist (SP6-11); however, this antagonism was non-competitive. Antagonistic properties of AWL-60 were also observed in vivo: in doses as low as 0.1 nmol/kg iv AWL-60 markedly attenuated the fall in blood pressure produced by [less than Glu]6SP6-11. Since AWL-60 exerts weak opioid agonistic properties (as a casomorphine analog) the possible involvement of an opioid agonistic component in their SP inhibitory action is considered.

Effect of prolonged administration of L-leucine-4-anti-pyrineamide dihydrochloride on certain organs and blood formation system in rat.

Newly synthesized L-leucine-4-antipyrineamide shows the biological effect of aminopyrine. In contrast, it does not cause any adverse effect on the growth of rat, and induces neither degeneration of the parenchymal organs nor agranulocytosis.

Effect of intracerebral administration of substance P on body temperature.

Effects of substance P (SP) administered into anterior hypothalamus or lateral ventricle on body temperature were investigated. When administered into lateral ventricle in doses from 20 to 2000 ng SP failed to influence body temperature. Application of SP into anterior hypothalamus in the same doses (20-2000 ng) resulted in a mild but insignificant increase in body temperature. No visible changes in the behavior of the rats, except slight sedation after the highest dose administered into lateral ventricle, were observed after application of SP. These results suggest that SP does not play any essential role in thermoregulation.

Pharmacological and metabolic studies on amino acid benzocaine derivatives.

Amino acid derivatives of benzocaine have shown local anesthetic properties similar to procaine in infiltration and block anesthesia tests, but were ineffective after topic application. Metabolic studies revealed the possibility of rapid hydrolysis of the derivatives to benzocaine by tissues and plasma hydrolyzing enzymes. Therefore they should be considered as prodrugs.

Analgesic and anti-inflammatory properties of 4-propionyl-4-(4-chlorophenyl)-1-(3-dimethylaminopropyl)-piperidine dihydrochloride.

4-propionyl-4-(4-chlorophenyl)-1-(3-dimethylaminopropyl)-piperidine dihydro-chloride (S8) showed in the hot plate test a marked analgesic activity with a better therapeutic index than that of pethidine. S8 possesses also anti-inflammatory (in short and long-term tests in vivo) as well as spasmolytic properties.

Synthesis and some biological properties of the hexapeptide analog of substance P with a C-terminal thioamide group.

A new hexapeptide analog of Substance P, containing a C-terminal thioamide group in the molecule [( Glp6, Mett11]SP6-11) was synthesized: Glp-Phe-Phe-Gly-Leu-Mett-NH2. Conversion to thioamide was accomplished from tert-butoxycarbonyl-L-methionine amide (Boc-Met-NH2) using Lawesson's Reagent. Its contracting activity on isolated guinea-pig ileum was considerably lower than that of [Glp6]SP6-11.

Analgesic activity of double endorphins in vivo.

The effects of double endorphins DALA2, DYNO2, CASO2 on pain threshold in the rats were compared with those of DALA (D-Ala2-Met5-enkephalinamide). Marked differences in the analgesic potency of the investigated peptides were noted. The most potent analgesic effect was exerted by DALA2. DYNO2 was weaker than DALA and DALA2 due to lack of glycine residue in position 3, probably responsible for the receptor affinity and analgesic activity in vivo. The weak analgesic activity of CASO2 in vivo corresponds with the weak opiate agonistic action of this peptide in vitro [see 7]. All investigated peptides induced changes in animal behaviour when injected i.c.v. The results indicated that among peptides in the novel group of double endorphins, DALA2 is of special interest because of a potent and long lasting analgesic action.

Synthesis of enkephalin analogs. Part VI. N,N-disubstituted derivatives.

Synthesis of four new N,N-disubstituted derivatives of enkephalin analogs: All2Tyr-DMet-Gly-Phe-epsilon Ahx-OMe 5, Bu2Tyr-DMet-Gly-Phe-epsilon Ahx-OMe 6, All2Tyr-DMet-Gly-Phe-epsilon Ahx-epsilon Ahx-OMe 11 and Bu2Tyr-DMet-Gly-Phe-epsilon Ahx-epsilon Ahx-OMe 12 is reported. they were tested for agonistic and antagonistic activity. Compound 5 is a little more potent agonist (IC50 = 1.9 x 10(-7) M/l, GPI) than compound 6(IC50 = 7.2 x 10(-7) M/l, GPI). They both are highly selective to mu receptor, because they show no trace of activity to delta receptor in concentration up to 10(-5) M/l. Compound 11 and 12 are less active and not selective as agonists. None of these compounds showed antagonistic activity.

Synthesis of enkephalin analogs. Part V. N-monosubstituted derivatives.

Synthesis of four new derivatives of enkephalin analogs: H-BuTyr-DMet-Gly- Phe-epsilon Ahx-OH 9, H-BzlTyr-DMet-Gly-Phe-epsilon Ahx-OH 12, H-Butyr-DMet-Gly- -Phe-epsilon Ahx-epsilon Ahx-OH 15 and H-BzlTyr-DMet-Gly-Phe-epsilon Ahx-OH is reported. They were examined for agonistic, antagonistic and analgesic activity. Compound 12 is the most potent among investigated peptides. Its agonistic activity in vitro is 7.85 x 10(-8) M/l (GPI) and 9.5 x 10(-7) M/l (MVD). None of the peptides showed antagonistic activity. Only compound 12 showed weak, not dose-dependent analgesic activity in rats.

Synthesis and preliminary pharmacological screening of 4-methylamino-2-phenylquinoline-3-carboxamides.

Eight new 4-methylamino-2-phenylquinoline-3-carboxamides were obtained. Three of them were screened pharmacologically and all turned out to be antiinflammatory, analgesic and sedative compounds. Their properties were compared to those of indomethacin and pethidine.