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PubMed1979

Stereospecific antidopaminergic and anticholinergic actions of the enantiomers of (+/-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine (CTC), a derivative of cyproheptadine.

(+/-)-CTC, a cyproheptadine derivative, possesses both antidopaminergic and anticholinergic activities which can be resolved, respectively, into its component (-)- and (+)-enantiomers. Both in vivo (antagonism of apomorphine-induced stereotypy, elevation of striatal homovanillic acid) and in vitro (inhibition of [3H]haloperidol binding), (-)-CTC was less active than haloperidol but more potent or equipotent compared to chlorpromazine. (+)-CTC was a more potent anticholinergic agent in vitro (inhibition of [3H]quinuclidinyl benzilate binding) than either thioridazine or clozapine, whereas in vivo (antagonism of the lethal action of physostigmine) the three compounds were similar. Comparison of the racemate with (-)-CTC in several in vivo test procedures to determine the influence of intrinsic anticholinergic activity showed that the presence of the anticholinergic (+)-enantiomer had little effect on the ability of (-)-CTC to antagonize apomorphine or elevate striatal homovanillic acid, whereas the activity of (-)-CTC was reduced in tests for postural asymmetry, avoidance and catalepsy. Stereoselectivity was also observed in terms of the alpha adrenergic blocking activity of CTC (inhibition of [3H]WB 4101 binding) which resides exclusively in the (-)-enantiomer. The ratios of (+)-CTC and (-)-CTC in terms of their anti-alpha adrenergic/antidopaminergic properties were large, suggesting a low propensity for the elicitation of orthostatic hypotension and sedation.

Adrenergic alpha-Antagonists↗
PubMed1983

Hypotensive action of a new benzimidazolinone derivative, threo-1-(2-hydroxy-2-(3,4,5-trimethoxyphenyl)-1-methylethyl)-4-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)piperidine (KF-4942): prazosin-like mode of action.

Among a series of benzimidazolinone derivatives, KF-4942 was examined on its mode of hypotensive action. It was found that KF-4942 was a potent hypotensive agent, and that the hypotension was produced mostly by alpha-adrenergic blockade. Alpha-adrenergic blocking action of KF-4942 was suggested to be selective to the postsynaptic receptor. Thus, KF-4942 was concluded to be an agent with properties similar to prazosin.

Adrenergic alpha-Antagonists↗
PubMed1995

Fentanyl-related 4-heteroanilido piperidine OHM3295 augments splenic natural killer activity and induces analgesia through opioid receptor pathways.

Recently, the fentanyl-related compound OHM3295 has been shown to induce a naltrexone-sensitive, dose-related analgesia in CD1 mice. However, unlike morphine or fentanyl, which are potent immunosuppressive drugs, OHM3295 has been found to augment splenic natural killer (NK) activity in a dose-related and naltrexone-reversible manner. The present study investigated the type (delta, kappa or mu) of opioid receptor involved in analgesia and immunomodulation after acute administration of OHM3295. CD1 mice pretreated with beta-funaltrexamine (beta-FNA, 40.0 mg/kg) showed an insignificant induction of analgesia (8.4 +/- 3.7%) after 3.2 mg/kg OHM3295, whereas mice pretreated with vehicle, norbinaltorphimine (10.0 mg/kg) or naltrindole (20.0 mg/kg) exhibited 43.6 +/- 12.6% of maximal analgesia, as determined by the tail-flick latency test. Consistent with previous results, acute administration of OHM3295 (3.2 mg/kg) augmented splenic NK activity (20.7 +/- 3.4 lytic units [LU]) relative to vehicle-treated mice (8.2 +/- 0.7 LU). Pretreatment with beta-FNA (40.0 mg/kg) completely blocked (9.0 +/- 1.9 LU) OHM3295-mediated augmentation of NK activity, whereas pretreatment with norbinaltorphimine (10.0 mg/kg) partially blocked (15.8 +/- 2.2 LU) the drug-induced effect. However, pretreatment with naltrindole (20.0 mg/kg) did not antagonize OHM3295-induced increases in splenic NK activity but rather further enhanced (32.3 +/- 4.2 LU) the effect. NK-enriched effector cells from OHM3295-treated mice displayed an increase in conjugation with YAC-1 target cells, an increase in the percent killing of target cells and a significant increase in the number of active killer cells compared with NK-enriched effector cells from vehicle-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1983

Metabolism of cadaverine and pipecolic acid in brain and other organs of the mouse.

Cadaverine and pipecolic acid metabolism was investigated in vitro in several organs of the mouse by measuring 14CO2 formation from labeled precursors. The liver showed the highest formation of 14CO2 from [1,5-14C]-cadaverine, whereas brain demonstrated a much lower formation. Anaerobiosis or inhibition of monoamineoxidase (MAO) activity significantly reduced 14CO2 formation in every organ, but inhibition of diamine oxidase (DAO) activity had no effect in brain and kidney. Piperidine was formed from cadaverine in vitro only in the large intestine and its content. This formation is probably of bacterial origin. Under a variety of experimental conditions we were unable to demonstrate any formation of piperidine in brain from cadaverine. Biosynthesis in vitro of [3H]-piperidine from D,L-[3H]-pipecolic acid was very low in brain and kidney. With the exception of brain and kidney, no other organs showed any formation of [3H]-piperidine. Neither MAO nor DAO inhibition influenced [3H]-piperidine formation in the large intestine with its content. Following 1 hr incubation at 37 degrees C under aerobic conditions, the levels of [14C]-pipecolic acid and [3H]-piperidine recovered from mouse brain homogenate did not indicate any significant degradation of these two substances. Our results suggest that under in vitro conditions, cadaverine is not a precursor of piperidine in brain, liver, heart, and kidney and that only very low levels of piperidine can be formed from pipecolic acid in brain. Outside the brain, formation of piperidine from pipecolic acid is detectable only in kidney and in the content of the large intestine. The latter is probably of bacterial origin. Our results do not support previous findings from other authors on an endogenous origin of piperidine in brain from cadaverine and pipecolic acid, and they suggest that a) cadaverine is not a precursor of piperidine in brain, b) the conversion of pipecolic acid into piperidine in the brain does not constitute a major metabolic pathway, and c) the main source of piperidine in the CNS may be of nonneural origin.

Animals↗
PubMed1991

[3H]DTG and [3H](+)-3-PPP label pharmacologically distinct sigma binding sites in guinea pig brain membranes.

The interaction of various compounds with sigma binding sites was examined in membranes prepared from whole guinea pig brain. Whereas [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine labeled a single population of binding sites exhibiting a Kd of 43 nM, [3H]1,3-di-o-tolylguanidine bound to two sites having Kds of 35 and 212 nM, and to a greater maximum number of sites than [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. Haloperidol, 1,3-di-o-tolylguanidine, BMY 14802, and (-)-pentazocine each displayed nearly equal affinity for binding sites labeled by [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H]1,3-di-o-tolylguanidine, whereas (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine was 3 times more potent in inhibiting [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding. In contrast, (+)-SKF 10,047, (+)-cyclazocine and (+)-pentazocine exhibited more than 9-fold higher affinity for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding sites. Dextromethorphan was 15-fold more potent against [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine, inhibited [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in a biphasic manner, and inhibited [3H]haloperidol and [3H](+)-SKF 10,047 binding with potencies similar to those obtained against [3H]1,3-di-o-tolylguanidine and [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, respectively. Phenytoin increased [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H](+)-SKF 10,047 binding, but did not enhance [3H]1,3-di-o-tolylguanidine or [3H]haloperidol binding. However, the potency of dextromethorphan to inhibit [3H]1,3-di-o-tolylguanidine binding was increased in the presence of phenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Novel spiropiperidines as highly potent and subtype selective sigma-receptor ligands. Part 1.

A series of spiro[[2]benzopyran-1,4'-piperidines] and spiro[[2]benzofuran-1,4'-piperidines] of general structure 10 is prepared, and the affinity for sigma(1)- and sigma(2)-receptors is investigated by means of radioligand binding assays. The synthesis of the spiropiperidines 14a and 23 proceeds from bromine/lithium exchange of the bromoacetals 11 and 21, addition to piperidin-4-one 12a, and subsequent cyclization. Systematic variations of the substituent R at the nitrogen atom, the group X in position 3, and the ring size of the oxygen heterocycle are performed. The sigma(1)- and sigma(2)-receptor affinities are determined with guinea pig brain and rat liver membrane preparations using [(3)H]-labeled (+)-pentazocine and ditolylguanidine, respectively. Test results show that a benzyl residue at the piperidine nitrogen atom and a methoxy group in position 3 are advantageous for high sigma(1)-receptor affinity. In this series the 1'-benzyl-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidine] (14a) and the 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] (23) are among the most potent sigma(1)-ligands interacting in the low nanomolar range with sigma(1)-receptors (14a, K(i) = 1.29 nM; 23, K(i) = 1.14 nM). Variation of the nitrogen substituent R from benzyl to H, alkyl, phenyl, or omega-phenylalkyl and the group X from methoxy to hydroxy, carbonyl, or alkyloxy led to reduced sigma(1)-receptor affinity. In addition to their high sigma(1)-receptor affinity, the spiropiperidines 14a and 23 display excellent selectivity toward sigma(2)-receptors (sigma(1)/sigma(2) = 2708 and 1130) and several other receptor and reuptake systems. Introduction of a polar hydroxy group in position 3 and elongation of the distance between the piperidine nitrogen atom and the phenyl moiety result in ligands with considerable sigma(2)-receptor affinity and therefore diminished sigma(1)/sigma(2)-receptor selectivity. The hemiacetalic 1'-(3-phenylpropyl)-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-3-ol (15e) represents the most active sigma(2)-receptor ligand in this series with a K(i) value of 83.1 nM.

Acetals↗
PubMed1989

Design, synthesis and SAR of analgesics.

A series of 4-phenylamidopiperidines having various substituents at the 4-position of the piperidine ring and the piperidine nitrogen were synthesized and tested. The antinociceptive activity of these compounds was measured by a modified hot-plate test. The active 4-phenylamidopiperidines have ED50 values ranging from 0.44 to 59 mg/Kg. High potency was observed among those compounds having an aralkyl substituent on the piperidine ring nitrogen. The highest Therapeutic Index value (TI = 223) was observed with N-[4-phenyl-1-(2-phenethyl)-4-piperidyl]-N-phenylpropanamide. Parameter Focusing using the regional fragment constants for the N-piperidine substituent (fL) and the C-4 piperidine substituent (fR') was successfully employed. The nature of the N-piperidine substituent is critical for activity, with the ideal fLo value at approximately 2.40. Structure-Activity Relationships indicate that the desired substituents for maximum enhancement of analgesic activity are an unsubstituted aromatic ring two carbons removed from the piperidine ring nitrogen and a small polar group able to hydrogen bond as a proton acceptor at the C-4 of the piperidine ring.

Analgesics↗
PubMed2001

Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors.

Novel piperidine-based bivalent ligands were prepared in enantiomerically pure form and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes). In this study, we have succeeded in using (1) the length of the linking chain connecting the two piperidine-based monomer units and (2) the absolute configuration of the piperidine monomer as a means to tailor activity and selectivity at the three monoamine transporters tested. In this series, the bivalent ligand 16, comprised of two (+)-trans-piperidine units linked by a pentamethylene spacer, exhibits a combination of high DA transporter (DAT) and 5-HT transporter (SERT) activity (K(i) = 39 nM and 7 nM, respectively). Piperidine 16 is capable of reducing cocaine's locomotor effects in mice while not having any effect on locomotion when tested alone. Additionally, compound 16 (1-10 mg/kg) does not substitute for cocaine in drug discrimination studies in rats. However, the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as lead candidates in the discovery of new therapeutics to treat a range of neurological disorders including cocaine addiction.

Animals↗