piperidines and 3-hydroxybenzylhydrazine

The quantitative structure-activity relationship between physicochemical properties and effects on dopamine (DA) synthesis and release in the rat brain, in a series of meta-substituted (S)-phenylpiperidines, has been investigated by means of partial least squares regression (PLS). The effect on DA synthesis caused by the drugs, in both non-pretreated and reserpine-pretreated rats, was assessed by measurements of tissue levels of L-DOPA accumulated in the striatum following treatment with a decarboxylase inhibitor. Assessment of effects on DA release was performed by analysis of perfusates collected from implanted microdialysis probes. The numerical characterization of the variation in physicochemical features of the phenylpiperidines used in the regression modeling was accomplished by using common tabulated aromatic and aliphatic substituent constants in combination with a set of property descriptors derived from molecular mechanics and semiempirical calculations. It was found that the biochemical responses could be accurately predicted by the regression models based on these molecular feature measures. The molecular features exerting influence on DA synthesis were found to be markedly different from those influencing DA release. This finding is discussed in terms of the possible existence of a dopamine receptor-mediated DA release-controlling mechanism, which may not involve the synthesis regulating DA D2 autoreceptor. Some findings regarding the impact of the piperidine N substituent on agonist properties of the drugs are reported. The regression models were also used for guidance in the search for a phenylpiperidine with a lower intrinsic activity, at the DA D2 type autoreceptor, than the partial DA agonist preclamol (3).

Topics: Animals; Autoreceptors; Brain; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Hydrazines; Ligands; Microdialysis; Piperidines; Rats; Receptors, Dopamine D2; Regression Analysis; Reserpine; Structure-Activity Relationship

Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic L-amino acid decarboxylase by means of NSD-1015, 100 mg kg-1 intraperitoneally. In animals treated with reserpine, 5 mg kg-1 subcutaneously -18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT1A receptor agonist 8-OH-DPAT, 0.15-2.4 mumol kg-1, whereas the partial dopamine D2 receptor agonist (-)3-PPP, 2.5-10.0 mumol kg-1, or the full dopamine D2 receptor agonist quinpirole, 0.05-0.8 mumol kg-1, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mumol kg-1, but not by (-)pindolol, 8 mumol kg-1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (-)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Corpus Striatum; Depression, Chemical; Dihydroxyphenylalanine; Dopamine; Ergolines; Hydrazines; Limbic System; Male; Naphthalenes; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Reserpine; Serotonin; Tetrahydronaphthalenes; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

Experiments were designed to distinguish between central and peripheral effects on temperature preference and body temperature of drugs injected intraperitoneally (IP) in infant mice ranging in age from 3 to 10 days postpartum. These compared a drug restricted to the periphery ("peripheral" drug) with a drug of similar action that reaches the central nervous system (CNS) as well as the periphery. Two different classes of drugs were utilized to test central versus peripheral actions independently with drugs that have different modes of action: 1-aromatic amino acid inhibitors and serotonin receptor antagonists. Although the decarboxylase inhibitor NSD 1015, which reaches the central nervous system from IP injection, can significantly decrease temperature preference (Tpref), the peripheral inhibitor carbidopa had no significant effects on Tpref or on body temperature (Tb). Furthermore, pretreatment with NSD 1015 prevented the elevation of Tpref produced by the serotonin precursor 5-hydroxytryptophan (5-HTP); however carbidopa pretreatment had no effect on the increased Tpref produced by 5-HTP. In other experiments, the peripheral serotonin antagonist BW 501C was not able to prevent elevated Tpref produced by 5-HTP, although the specific 5-HT2 antagonist pirenperone, which reaches the CNS as well as the periphery, blocks the 5-HTP elevation of Tpref. Taking all of these results together, we conclude that the changes in Tb and Tpref following these treatments require a decarboxylase inhibitor or 5-HT antagonist that reaches the CNS. However, the well known and potent peripheral vasoconstrictor action of serotonin requires that peripheral effects of drugs be considered when manipulations are not restricted to the CNS.

Topics: 5-Hydroxytryptophan; Aging; Amidines; Animals; Behavior, Animal; Body Temperature; Body Temperature Regulation; Carbidopa; Carboxy-Lyases; Central Nervous System; Double-Blind Method; Drug Interactions; Hydrazines; Injections, Intraperitoneal; Mice; Peripheral Nerves; Piperidines; Serotonin Antagonists

The irreversible dopamine (DA) receptor antagonist N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the extent of receptor reserve at DA autoreceptors regulating in vivo tyrosine hydroxylase activity. Rats were treated with vehicle or EEDQ (1 X 0.5-2 X 6 mg/kg, subcutaneously) and, 24 hr later, dose response curves were generated for DA agonist reversal of gamma-butyrolactone-induced striatal L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation. Double reciprocal plots were obtained of equieffective doses of agonist required to elicit response at several levels of effect before and after partial irreversible receptor inactivation. A pseudo-dissociation constant (pseudo-KA, in units of dose) and the fraction of receptors remaining active (q) were determined; these values were then used to calculate the relationship between receptor occupancy and response. The ED50 (1 microgram/kg) for the full DA receptor agonist N-propylnorapomorphine (NPA) was shifted 2.8, 4.8-, and 11.3-fold to the right after partial irreversible receptor blockade which left the fraction of receptors remaining active (q) at 0.37, 0.17 and 0.058, respectively. Corresponding maximal reversal of L-DOPA accumulation was 100, 77, and 58%, indicating a nonlinear relationship between receptor occupancy and response for NPA and the presence of a large receptor reserve; maximal and half-maximal responses were calculated to require occupancy of 30 and 3.8% of the total receptor pool, respectively. Dose response curves were also obtained for the DA autoreceptor-selective agents EMD 23,448 and (+)- and (-)-3-PPP before and after EEDQ treatment. In controls, EMD 23,448 and (+)-3-PPP, like NPA, completely reversed striatal gamma-butyrolactone-induced L-DOPA accumulation, whereas the maximal effect of (-)-3-PPP was 52% reversal. After EEDQ treatment (6 mg/kg), EMD 23,448 and (+)-3-PPP showed relatively small shifts in ED50 values. Furchgott analysis demonstrated that all three atypical agents are partial agonists at the DA autoreceptor with efficacies of 0.19 (EMD 23,448), 0.12 [(+)-3-PPP], and 0.05 [(-)-3-PPP] relative to NPA. The presence of a larger receptor reserve at pre-versus postsynaptic D2 DA receptors and the partial agonist character of drugs such as EMD 23,448 and the enantiomers of 3-PPP may account for their autoreceptor selectivity.

Topics: 4-Butyrolactone; Adrenergic alpha-Antagonists; Animals; Apomorphine; Corpus Striatum; Dihydroxyphenylalanine; Homeostasis; Hydrazines; Levodopa; Male; Piperidines; Quinolines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The mechanism of action of 5-hydroxytryptophan (5-HT, 10 mg/kg), quipazin (7 mg/kg), zimelidin (15 mg/kg) and m-chlorophenylpiperazine (5 mg/kg) was examined with the aid of some analyzer substances. The avoidance behavior under stress was used as criterion of estimation. The optimizing effect of 5-HT on the avoidance behavior was demonstrated to be a consequence of serotonin synthesis activation and its release with activation of postsynaptic 5-HT-1-receptors. An adverse effect of quipazin on the avoidance behavior was, to a greater degree, due to the activation of 5-HT-2-autoreceptors rather than of dopamine receptors. The inhibitory effect of m- chlorphenylpiperazine was reversed by administration of pyrenepyrone , a blocker of 5-HT-2-receptors. The inhibitory effect of zimelidine on the avoidance behavior was not removed by clonidin . The positive effect on the avoidance behavior under stress occurs as a result of exposures that activate the synthesis and release of 5-HT as well as of activation of postsynaptic 5-HT-1 receptors.

Topics: 5-Hydroxytryptophan; Acute Disease; Animals; Avoidance Learning; Cyproheptadine; Humans; Hydrazines; Male; Piperazines; Piperidines; Quinolines; Quipazine; Rats; Rats, Inbred Strains; Stress, Psychological; Tranquilizing Agents; Zimeldine