Quaternised renzapride as a potent and selective 5-HT4 receptor agonist

Baxter, G.S.; Boyland, P.; Gaster, Laramie M.; King, Frank D.

doi:10.1016/s0960-894x(01)81243-9

Cited by 13 publications

(6 citation statements)

References 11 publications

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“…They are similar in potency to ML 10302, an ester analogue of RS 23597, shown by Langlois et al (1994) and the present study to act as a partial agonist. In contrast to several other 5-HT4 receptor agonists, including SB 205149 (Baxter et al, 1993), SC 53116 (Flynn et al, 1993), RS 67333 and RS 67506 were selective toward the 5-HT4 receptor (Table 2). RS 67333 and RS 67506 acted as partial 5-HT4 receptor agonists in rat oesophagus; a property that appears to be true for most non-indole 5-HT4 receptor agonists (Table 3).…”

Section: Discussionmentioning

confidence: 92%

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Eglen¹,

Bonhaus²,

Johnson³

et al. 1995

British J Pharmacology

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1 The pharmacology of two novel 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxy phenyl)-3-[1(n-butyl)-4-piperidinyl]-1-propanone HCl) and RS 67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone HCl) have been assessed in vitro and in vivo.2 RS 67333 and RS 67506 exhibited affinities (pKi=8.7 and 8.8, respectively) for the 5-HT4 binding sites, labelled with [3H]-GR 113808, in guinea-pig striatum. The Hill coefficients from these displacement curves were not significantly different from unity. The compounds exhibited lower affinities (< 6.0) at several other receptors including 5-HTA, 5-HTID, 5-HT2A, 5-HT2c, dopamine D,, D2 and muscarinic M,-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the a, (pKi=8.9 and 7.9, respectively) and Ca2 (pK,=8.0 and 7.3, respectively) binding sites. 3 At the 5-HT4 receptor mediating relaxation of the carbachol-precontracted oesophagus, RS 67333 and RS 67506 acted as potent (pECm 8.4 and 8.6, respectively), partial agonists (intrinsic activities, with respect to 5-HT were 0.5 and 0.6, respectively) with respect to 5-HT. Relaxant responses to RS 67333 or RS 67506 were surmountably antagonized by GR 113808 (10 nM), with apparent affinities (pKB) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose-dependent increases in heart rate of the anaesthetized micropig (ED50 4.9 and 5.4 pg kg-',i.v.), with maximal increases of 35 and 47 beats min-', respectively. 4 RS 67333 and RS 67506, therefore, acted as potent, partial 5-HT4 receptor agonists in vitro and in vivo. These compounds, by virtue of their high potency and selectivity, may have some utility in elucidating the physiological role of 5-HT4 receptors.

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Section: Discussionmentioning

confidence: 92%

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Eglen¹,

Bonhaus²,

Johnson³

et al. 1995

British J Pharmacology

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“…These benzamides are found to be non-selective and always have antagonistic activity at the 5-HT3 receptor (zacopride, renzapride and metoclopramide). Structural modification of the basic chain of the benzamides, cisapride SB 205149 and SC 53116 lead to the identification of more potent 5-HT4R agonists with lower affinity for 5-HT3 than the first generation benzamides [59][60][61]. Nevertheless, cisapride has appreciable affinity for 5-HT2A and a1-adrenergic receptors.…”

Section: Iv-1 Agonistsmentioning

confidence: 99%

5-HT4 Receptors

Bockaert¹,

Claeysen

Compan³

et al. 2004

CDTCNSND

166

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Serotonin 4 receptors (5-HT(4)Rs) were discovered 15 years ago. They are coded by a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminal variants (a, b, c, d, e, f, g, n). Their sequences differ after position L(358). Another variant is characterized by a 14 residue insertion within the extracellular loop 2. Highly selective potent 5-HT(4) receptor antagonists and partial agonists which cross the blood-brain barrier have been synthesized, but a specific full agonist for brain studies is still missing. Based on physiological and behavioral experiments, 5-HT(4)Rs may be targets to treat cognitive deficits, abdominal pain and feeding disorders. One 5-HT(4)R-directed drug (SL65.0155) is already in phase II to treat patients suffering from memory deficits or dementia.

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“…In recent years, several reports have described new compounds with 5-HT 4 receptor agonist activity possessing better selectivity than the previous compounds. Thus SC-53116 ( 6 ), the quaternized butyl derivative of renzapride, and a macrocyclic compound 28 were the first reported benzamides which surpassed the selectivity of the other benzamides for this receptor. ML 10302 ( 7a ), a compound structurally closely related to 1 , was also shown by us to be a selective 5-HT 4 receptor agonist 29 with nanomolar affinity in the electrically-evoked contraction model in the guinea pig ileum, while 5-HT 4 receptor antagonist properties have been reported previously. , More recently, several ketone derivatives 32 and some potent carbazimidamines 17a,b were reported as selective and metabolically-stable 5-HT 4 receptor agonists.…”

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confidence: 99%

New Esters of 4-Amino-5-chloro-2-methoxybenzoic Acid as Potent Agonists and Antagonists for 5-HT₄ Receptors

et al. 1997

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A number of benzoates derived from 4-amino-5-chloro-2-methoxybenzoic acid and substituted 1-piperidineethanol were synthesized and found to be potent 5-HT4 receptor agonists in the electrically-stimulated myenteric plexus and longitudinal muscle of the guinea pig ileum and the rat esophagus muscle. Monosubstitution of the piperidine ring with Me, OH, NH-Ac, or CONH2 groups gave compounds equipotent to 7a (ML 10302), a 5-HT4 receptor agonist previously reported to have nanomolar affinity. 7a,k were as potent as serotonin (5-HT) but had maximal responses which were only 60-80% of that of 5-HT, suggesting a partial agonist profile for these compounds. Binding assays were performed with [3H]GR 113808 in the rat striatum, and several of these compounds were found to have nanomolar affinity for 5-HT4 receptors (7a, Ki = 1.07 +/- 0.5 nM; 7k, Ki = 1.0 +/- 0.3 nM). The introduction of two methyl groups on the piperidine ring brought about a dramatic change in the pharmacological profile of 2-[(cis- and trans-3,5-dimethylpiperidinyl)ethyl]-4-amino-5-chloro-2- methoxybenzoate, 7g,h. 7g (Ki = 0.26 +/- 0.06 nM) inhibited the relaxant action of 5-HT in the rat esophagus muscle with a pA2 value of 8.6. The advantage of the ester function was demonstrated by comparing the activity of several such compounds at 5-HT4 receptors with those of the corresponding amidic derivatives. This difference was less marked when the basic moiety was sterically constrained as in the quinuclidine and tropane moieties. Structural analyses of 7a,g were performed by determining their X-ray crystal structures and by molecular modeling (SYBYL). A relatively limited number of minimum energy conformers was found for both compounds. They were characterized by the cis folded conformation of the ethyl chain and by the orientation of the lone pair of the nitrogen atom pointing out of the molecule as seen in conformationally-constrained benzamides such as zacopride and renzapride. A hypothetical model for the 5-HT4 receptor with two sites for the binding of agonist and antagonist molecules was proposed.

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Quaternised renzapride as a potent and selective 5-HT4 receptor agonist

Cited by 13 publications

References 11 publications

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

5-HT4 Receptors

New Esters of 4-Amino-5-chloro-2-methoxybenzoic Acid as Potent Agonists and Antagonists for 5-HT₄ Receptors

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Quaternised renzapride as a potent and selective 5-HT4 receptor agonist

Cited by 13 publications

References 11 publications

Pharmacological characterization of two novel and potent 5‐HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Pharmacological characterization of two novel and potent 5‐HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

5-HT4 Receptors

New Esters of 4-Amino-5-chloro-2-methoxybenzoic Acid as Potent Agonists and Antagonists for 5-HT4 Receptors

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About

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

New Esters of 4-Amino-5-chloro-2-methoxybenzoic Acid as Potent Agonists and Antagonists for 5-HT₄ Receptors