Antinociceptive profile of the new nicotinic agonist DBO-83

Ghelardini, Carla; Galeotti, Nicoletta; Barlocco, Daniela; Bartolini, Alessandro

doi:10.1002/(sici)1098-2299(199703)40:3<251::aid-ddr5>3.0.co;2-j

Cited by 20 publications

(11 citation statements)

References 17 publications

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“…Thus, the antinociceptive properties of 1a appear to be nAChR-mediated. 13 Moreover, 1a has the potential of producing antinociceptive effects in vivo without the potential life-threatening side effects presented by (()-epibatidine (i.e., cardiovascular pressor effects and seizures) 14 due to the lack of agonist activity at the neuromuscular junction. Finally, the results of the modeling indicate that 1a presents one conformation (1C) similar to that of epibatidine.…”

Section: Discussionmentioning

confidence: 99%

Mono- and Disubstituted-3,8-diazabicyclo[3.2.1]octane Derivatives as Analgesics Structurally Related to Epibatidine: Synthesis, Activity, and Modeling

et al. 1998

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A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate assay, the majority of the compounds showed significant effects, the most interesting being the 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals. Administration of naloxone (1 mg/kg ip) did not antagonize its antinociception while mecamylamine (2 mg/kg ip) did, thus suggesting the involvement of the nicotinic system in its action. Binding studies confirmed high affinity for the R 4 2 nAChR subtype (K i ) 4.1 ( 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of any activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds were compared from a structural and conformational point of view through theoretical calculations and high-field 1 H NMR spectroscopy. Results indicate that all of them present one conformation similar to that of epibatidine.

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Section: Discussionmentioning

confidence: 99%

Mono- and Disubstituted-3,8-diazabicyclo[3.2.1]octane Derivatives as Analgesics Structurally Related to Epibatidine: Synthesis, Activity, and Modeling

et al. 1998

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“…The final members of this class to be discussed are the recently reported analgesic nicotinics pharmacologically characterized by Barlocco and coworkers [180]. These compounds are based on modification of benzo[h]cinnolines and possess Members of Class D contain an acyclic HBA/π moiety and a cationic site that is cyclic (Table V).…”

Section: Ii4b Class B: Cyclic Hba/π Acyclic Cationmentioning

confidence: 99%

Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

Schmitt

2000

CMC

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Nicotinic acetylcholine receptors (nAChRs) are the subject of ever increasing interest because of their presumed involvement in the etiology of numerous clinical disorders. Unfortunately, the absence of atomic-level structural data, as well as the pharmacological complexity of these receptors leaves many fundamental questions unanswered. An understanding of how ligands interact with the receptor and, in-turn, how these interactions lead to pharmacological effect is vital in the advancement of nAChR-based therapeutics. We will first explore physico-chemical themes that are evidenced to be of particular importance in nAChR molecular recognition; these are- pi-cation interaction, conformational entropy and stereochemistry. The second objective of this review is an interpretive encapsulation of the extensive and disparate body of structure-activity data that now exists for nAChRs. Finally, this review will advocate a re-investigation of distance geometry based methods as well as the need for additional approaches in nicotinic receptor pharmacophore generation.

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“…The doses and administration schedules of the above-mentioned drugs were ideal for preventing antinociceptions induced, respectively, by morphine , the GABA B agonist baclofen [Malcangio et al, 1991], nicotine [Ghelardini et al, 1997], and amphetamine [Bartolini et al, 1987].…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive profile of the natural cholinesterase inhibitor huperzine A

Galeotti

Ghelardini

Mannelli

et al. 2001

Drug Development Research

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The antinociceptive effect of huperzine A, a novel cholinesterase inhibitor, was investigated in the mouse hot-plate and abdominal constriction tests. Huperzine A induced a dose-dependent antinociception (70-110 µg kg -1 i.p.) which was prevented by scopolamine (0.1 mg kg -1 i.p.) and S-(-)-ET 126 (0.01 µg per mouse i.c.v.), but not by naloxone (1 mg kg -1 i.p.), mecamylamine (2 mg kg -1 i.p.), α-methyl-p-tyrosine (100 mg kg -1 i.p.), or CGP 35348 (100 mg kg -1 i.p.). A dose-dependent inhibition of the antinociception induced by huperzine A (110 µg kg -1 i.p.) was observed after inactivation of the M 1 gene by an antisense oligodeoxyribonucleotide (aODN). This effect was detected 24 h after the last intracerebroventricular injection of aODN. Time-course experiments revealed that, after the end of the aODN treatment, sensitivity to analgesic drugs progressively appeared, reaching the normal range at 96 h. Huperzine A, at the maximal effective doses, did not produce any alteration of mice motor coordination, as revealed by rota-rod experiments. These results indicate that huperzine A is endowed by muscarinic antinociceptive properties mediated by the activation of central M 1 muscarinic receptor subtype. Drug Dev. Res. 54:19-26, 2001.

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Antinociceptive profile of the new nicotinic agonist DBO-83

Cited by 20 publications

References 17 publications

Mono- and Disubstituted-3,8-diazabicyclo[3.2.1]octane Derivatives as Analgesics Structurally Related to Epibatidine: Synthesis, Activity, and Modeling

Mono- and Disubstituted-3,8-diazabicyclo[3.2.1]octane Derivatives as Analgesics Structurally Related to Epibatidine: Synthesis, Activity, and Modeling

Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

Antinociceptive profile of the natural cholinesterase inhibitor huperzine A

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