Synthesis and Biological Activities of (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and Its Metabolites

Heier, Richard F.; Dolak, Lester A.; Duncan, J. Neil; Hyslop, Deborah K.; Lipton, M. F.; Martin, Iain; Mauragis, M. A.; Piercey, Montford F.; Nichols, Nanette F.; Schreur, P. J. K. D.; Smith, Martin; Moon, Malcolm W.

doi:10.1021/jm960360q

Cited by 72 publications

(54 citation statements)

References 16 publications

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“…The selectivity ratios obtained for the seven D3-preferring agonists, as calculated from the M.E.D.s for the induction of yawning and hypothermia, range from 3.2 to 32.0, indicating that these agonists were more potent at inducing yawning behavior than in producing hypothermia. Unlike the other D2/D3 agonists, the currently available in vitro data suggests that sumanirole preferentially binds the D2 over D3 receptor (Piercey et al 1996;Heier et al 1997), and in the current studies sumanirole displayed a distinctly different profile of activity. Not only was sumanirole more potent at inducing hypothermia than yawning, but as will be discussed later, the low levels of yawning produced by sumanirole may not be mediated through the D3 receptor, and therefore the M.E.D.…”

Section: Agonist-induced Yawning Behavior and Hypothermiamentioning

confidence: 44%

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

et al. 2007

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Rationale-Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases.Objectives-These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia.Correspondence to: James H. Woods. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl) Methods-The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed, and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 as well as sumanirole-induced hypothermia.Results-D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia, and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride's profile of action was more similar to the D2 antagonists than to the D3 antagonists.Conclusions-D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors.

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Section: Agonist-induced Yawning Behavior and Hypothermiamentioning

confidence: 44%

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

et al. 2007

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“…The effect of the selective D 2 receptor agonist PNU-95666E (Heier et al, 1997) was investigated in rats at the doses of 0.1, 0.3, 1, and 3 mol/kg. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4, the s.c. administration of PNU-95666E did not facilitate penile erection. PNU-95666E has been reported as a centrally acting D 2 agent on dopaminergic neurons in rats and mice after systemic administration (Durhama et al, 1997;Heier et al, 1997;Sethy et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

“…A number of studies have also reported that in rats, dopamineinduced penile erection seems to involve, particularly, the D 2 -like receptor subtypes, and this seems to be the case also in humans (Heaton, 2000;Andersson and Hedlund, 2002). PNU-95666E is a centrally acting agonist that reportedly activates the D 2 receptor in central dopamine neurons, increases striatal acetylcholine concentrations, and decreases cerebellar nucleotides in rats and mice after systemic administration (Durhama et al, 1997;Heier et al, 1997;Sethy et al, 1997). PNU-95666E, which does not induce penile erection (Fig.…”

Section: Discussionmentioning

confidence: 97%

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Central Mechanisms Regulating Penile Erection in Conscious Rats: The Dopaminergic Systems Related to the Proerectile Effect of Apomorphine

Hsieh¹,

Hollingsworth²,

Martino³

et al. 2003

J Pharmacol Exp Ther

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Apomorphine has been used as a pharmacological probe of dopaminergic receptors in a variety of central nervous system disorders. The utility of apomorphine as an agent for the treatment of erectile dysfunction has also been demonstrated clinically. Apomorphine is a nonselective dopaminergic receptor agonist with potent binding affinity (K i ) of 101, 32, 26, 2.6, and 10 nM for D 1 , D 2 , D 3 , D 4 , and D 5 , respectively. When administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.), apomorphine fully evoked penile erections in conscious rats with maximum effect at 0.1 mol/kg s.c. and 3 nmol/rat i.c.v., respectively. Apomorphine was less efficacious when injected intrathecally (i.t.) to L4-L6 spinal levels (50% at 30 -100 nmol/rat i.t.). Penile erection facilitated by apomorphine was blocked by haloperidol and clozapine (i.p. and i.c.v.) but not by domperidone (a peripherally acting dopaminergic receptor antagonist). In this model using conscious rats, penile erection was significantly induced by quinpirole (D 2 -D 3 -D 4 receptor agonist), but not by R(ϩ)

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“…PG01037 preferentially occupies D3-rich regions over D2-rich regions as illustrated by pharmacologic magnetic resonance imaging (Grundt et al, 2007b) and is at least twice as D3-selective compared with other antagonists such as NGB2904. To further investigate the contribution of these receptor subtypes, the capacities of the D3-preferring agonist PD128907 (ϳ13-fold D3/D2 selectivity; Pugsley et al, 1995) and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate] (ϳ200-fold D2/D3 selectivity; Heier et al, 1997) to substitute for the DS and priming effects of cocaine were compared. The effects of PG01037 and L-741626 on cocaine and these selective DA agonists were evaluated in squirrel monkeys trained to: 1) discriminate cocaine from saline; 2) self-administer cocaine or food under a second-order fixed-interval (FI), fixed-ratio (FR) schedule of reinforcement; and 3) reinstate cocaine-seeking behavior by cocaine priming after extinction.…”

mentioning

confidence: 99%

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

Achat-Mendes

Grundt

Cao

et al. 2010

J Pharmacol Exp Ther

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Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferr- were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine-and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine.Cocaine inhibits the reuptake of DA into presynaptic terminals, resulting in stimulation of DA receptors primarily located in motor and limbic brain systems. Within the D2 family of DA receptors, there is substantial evidence for the role of the D2 receptor subtype in cocaine-induced behaviors; however, this research has not generated successful candidates for the treatment of cocaine addiction (see Xi and Gardner, 2008 for review). Considerably less is understood about the function of the D3 receptor subtype, primarily because of a lack of selective pharmacological probes that

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Synthesis and Biological Activities of (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and Its Metabolites

Cited by 72 publications

References 16 publications

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

Central Mechanisms Regulating Penile Erection in Conscious Rats: The Dopaminergic Systems Related to the Proerectile Effect of Apomorphine

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

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