440:
471:
501:
456:
486:
353:
122:
439:
149:, meaning it doesn't need the agonist it modulates to yield agonistic effects. Also, modulation may not affect the affinities or efficacies of different agonists equally. If a group of different agonists that should have the same action bind to the same receptor, the agonists might not be modulated the same by some modulators.
157:
A modulator can have 3 effects within a receptor. One is its capability or incapability to activate a receptor (2 possibilities). The other two are agonist affinity and efficacy. They may be increased, lowered or left unaffected (3 and 3 possibilities). This yields 17 possible modulator combinations.
360:
Some modulators act to stabilize conformational changes associated with the agonist-bound state. This increases the probability that the receptor will be in the active conformation, but does not prevent the receptor from switching back to the inactive state. With a higher probability of remaining in
125:
Orthosteric agonist (A) binds to orthosteric site (B) of a receptor (E). Allosteric modulator (C) binds to allosteric site (D). Modulator increases/lowers the affinity (1) and/or efficacy (2) of an agonist. Modulator may also act as an agonist and yield an agonistic effect (3). Modulated orthosteric
402:
Modulators can directly regulate receptors rather than affecting the binding of the agonist. Similar to stabilizing the bound conformation of the receptor, a modulator that acts in this mechanism stabilizes a conformation associated with the active or inactive state. This increases the probability
548:
risk relative to similarly acting orthosteric drugs. It may also allow a strategy where doses large enough to saturate receptors can be taken safely to prolong the drug effects. This also allows receptors to activate at prescribed times (i.e. in response to a stimulus) instead of being activated
448:
s shift initial agonist response curve (solid curve) to lower agonist concentrations by increasing affinity and/or increase maximum response by increasing efficacy. Dashed curves are 2 examples out of many possible curves after PAM addition. Arrows show the approximate direction of the shifts in
389:
of a receptor. Desensitization prevents a receptor from activating, despite the presence of an agonist. This is often caused by repeated or intense exposures to an agonist. Eliminating or reducing this phenomenon increases the receptor's overall activation. AMPA receptors are susceptible to
75:), or both. Negative types decrease the agonist affinity and/or efficacy. Neutral types don't affect agonist activity but can stop other modulators from binding to an allosteric site. Some modulators also work as allosteric agonists and yield an agonistic effect by themselves.
485:
470:
411:. Lower pH increases the stability of the inactive state, and thereby decreases the sensitivity of the receptor. It is speculated that the changes in charges associated with adjustments to pH cause a conformational change in the receptor favoring inactivation.
426:
Efficacy increasing modulators increase maximum efficacy of partial agonists. Full agonists already activate receptors fully so modulators don't affect their maximum efficacy, but somewhat shift their response curves to lower agonist concentrations.
500:
455:
532:
doesn't often favor such changes. Allosteric sites are less important for receptor function, which is why they often have great variation between related receptors. This is why, in comparison to orthosteric drugs, allosteric drugs can be very
1183:
Li Y, Sun L, Yang T, Jiao W, Tang J, Huang X, et al. (January 2019). "Design and
Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice".
552:
Modulators affect the existing responses within tissues and can allow tissue specific drug targeting. This is unlike orthosteric drugs, which tend to produce a less targeted effect within body on all of the receptors they can bind to.
713:
Neubig RR, Spedding M, Kenakin T, Christopoulos A (December 2003). "International Union of
Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology".
299:
Due to the variety of locations on receptors that can serve as sites for allosteric modulation, as well as the lack of regulatory sites surrounding them, allosteric modulators can act in a wide variety of mechanisms.
142:) of the receptor. This will often cause the orthosteric site to also change, which can alter the effect of an agonist binding. Allosteric modulators can also stabilize one of the normal configurations of a receptor.
66:
Allosteric modulators can be 1 of 3 types either: positive, negative or neutral. Positive types increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e.
537:, i.e. target their effects only on a very limited set of receptor types. However, such allosteric site variability occurs also between species so the effects of allosteric drugs vary greatly between species.
373:
will deactivate slower, and facilitate more overall cation transport. This is likely accomplished by aniracetam or CX614 binding to the back of the "clam shell" that contains the binding site for
266:
don't affect agonist activity, but bind to a receptor and prevent PAMs and other modulators from binding to the same receptor thus inhibiting their modulation. Neutral modulators are also called
419:
Modulators that increase only the affinity of partial and full agonists allow their efficacy maximum to be reached sooner at lower agonist concentrations – i.e. the slope and plateau of a
1227:. Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science (Satellite to the 2011 Meeting of the Society for Neuroscience).
494:
s shift curves to higher concentrations by decreasing affinities and/or lower maximum responses by decreasing efficacies. If compared to PAMs, the effects of NAMs are inverse.
110:
is the ability of a substance to activate a receptor, given as a percentage of the ability of the substance to activate the receptor as compared to the receptor's endogenous
98:
Allosteric modulators can alter the affinity and efficacy of other substances acting on a receptor. A modulator may also increase affinity and lower efficacy or vice versa.
1319:
Svensson KA, Hao J, Bruns RF (2019). "Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders".
568:
Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals. These include:
312:
change in their target receptor which increases the binding affinity and/or efficacy of the receptor agonist. Examples of such modulators include
975:"Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery"
479:
increase agonist affinities and shift their curves to lower concentrations, but as they work as antagonists, they also lower maximum responses.
321:
1386:
658:
653:
648:
509:
work like NAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.
464:
work like PAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.
1221:"Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations"
1840:
394:
has been shown to stabilize this interface and slow desensitization, and is therefore considered a positive allosteric modulator.
593:
283:
618:
614:
936:
838:
766:
690:
560:, for example, quickly desensitize in the presence of agonist drugs, but maintain normal function in the presence of PAMs.
1993:
1937:
1646:
1336:
1140:
Lu S, He X, Ni D, Zhang J (July 2019). "Allosteric
Modulator Discovery: From Serendipity to Structure-Based Design".
1124:
1091:
1830:
1379:
557:
2012:
1926:
1998:
1820:
1474:
1468:
90:
changes within receptors caused by the modulators through which the modulators affect the receptor function.
1270:"mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning"
1987:
1759:
973:
Melancon BJ, Hopkins CR, Wood MR, Emmitte KA, Niswender CM, Christopoulos A, et al. (February 2012).
403:
that the receptor will conform to the stabilized state, and modulate the receptor's activity accordingly.
1902:
1675:
1372:
161:
For all practical considerations, these combinations can be generalized only to 5 classes and 1 neutral:
2076:
1741:
1580:
1567:
1538:
1483:
540:
Modulators can't turn receptors fully on or off as modulator action depends on endogenous ligands like
386:
356:
CX614, a PAM for an AMPA receptor binding to an allosteric site and stabilizing the closed conformation
216:
work like PAMs, but also function as antagonists and lower the efficacy of the agonists they modulate.
2037:
1554:
606:
340:
and increase the channel opening frequency, but not the duration of each opening. Barbiturates like
1931:
1877:
1862:
1834:
1615:
1610:
1601:
404:
309:
201:
139:
87:
2032:
2003:
1971:
1801:
1606:
1562:
1513:
1444:
107:
103:
99:
72:
68:
32:
758:
1913:
1719:
556:
Some modulators have also been shown to lack the desensitizing effect that some agonists have.
528:
within this site may especially lower receptor function. This can be harmful to organisms, so
2044:
1888:
1621:
1508:
643:
134:. Modulators don't bind to this site. They bind to any other suitable sites, which are named
60:
2049:
1893:
1746:
1699:
534:
8:
1670:
1458:
1268:
Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, et al. (August 2009).
420:
115:
1897:
1866:
1597:
1493:
1296:
1269:
1245:
1220:
1165:
1116:
1083:
999:
974:
947:
928:
912:
885:
860:
830:
751:
377:, stabilizing the closed conformation associated with activation of the AMPA receptor.
352:
1966:
1871:
1694:
1487:
1350:
1342:
1332:
1301:
1250:
1201:
1157:
1120:
1087:
1049:
1024:""Selective" Class C G Protein-Coupled Receptor Modulators Are Neutral or Biased mGlu
1004:
952:
932:
890:
834:
762:
731:
686:
573:
287:
1169:
1956:
1750:
1665:
1419:
1324:
1291:
1281:
1240:
1232:
1193:
1149:
1112:
1079:
1039:
994:
986:
942:
924:
880:
876:
872:
826:
723:
541:
185:
86:, "solid" or "shape". This can be translated to "other shape", which indicates the
602:
reducing the intensity of sleep disorders by positively regulating GABA receptors.
138:. Upon binding, modulators generally change the three-dimensional structure (i.e.
1884:
1796:
1634:
1629:
1499:
1463:
1453:
1436:
1197:
1153:
344:
bind β domains and increase the duration of each opening, but not the frequency.
258:
work like NAMs, but also as agonists with and without the agonists they modulate.
210:
work like PAMs, but also as agonists with and without the agonists they modulate.
146:
1328:
1022:
Hellyer SD, Albold S, Wang T, Chen AN, May LT, Leach K, et al. (May 2018).
524:
Related receptors have orthosteric sites that are very similar in structure, as
1576:
1431:
1414:
313:
189:
173:
40:
36:
1236:
2070:
1812:
1711:
1703:
1686:
1625:
1346:
610:
577:
432:
391:
390:
desensitization via a disruption of a ligand-binding domain dimer interface.
362:
341:
1791:
1657:
1640:
1395:
1354:
1305:
1254:
1205:
1161:
1053:
1044:
1023:
1008:
956:
894:
859:
Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM (September 2005).
823:
Pharmacology in drug discovery and development: understanding drug response
735:
544:, which have limited and controlled production within body. This can lower
245:
44:
24:
20:
145:
In practice, modulation can be complicated. A modulator may function as a
1948:
1921:
1854:
1547:
1427:
626:
337:
317:
241:
1286:
1774:
1589:
366:
197:
181:
121:
990:
861:"Mechanism of positive allosteric modulators acting on AMPA receptors"
727:
1783:
1733:
1364:
622:
529:
374:
229:
16:
Substance that binds to a receptor to change its response to stimuli
1824:
545:
525:
329:
177:
172:) increase agonist affinity and/or efficacy. Clinical examples are
712:
158:
There are 18 (=2*3*3) if neutral modulator type is also included.
35:
to change that receptor's response to stimuli. Some of them, like
1448:
237:
111:
52:
126:
agonist affects the receptor (4). Receptor response (F) follows.
47:
drugs. The site that an allosteric modulator binds to (i.e., an
1961:
1530:
1410:
581:
613:
by positively modulating dopamine receptors. Examples include
431:
Receptor response % as a function of logarithmic agonist
1076:
Biased signaling in physiology, pharmacology and therapeutics
549:
constantly by an agonist, irrespective of timing or purpose.
370:
361:
the active state, the receptor will bind agonist for longer.
1323:. Advances in Pharmacology. Vol. 86. pp. 273–305.
397:
249:
233:
130:
The site to which endogenous agonists bind to is named the
972:
680:
599:
reducing anxiety by positively modulating GABA receptors.
71:), increasing its ability to activate the receptor (i.e.
917:
Progress in
Molecular Biology and Translational Science
408:
78:
The term "allosteric" derives from the Greek language.
59:). Modulators and agonists can both be called receptor
1267:
282:). An example is 5-methyl-6-(phenylethynyl)-pyridine (
114:. If efficacy is zero, the substance is considered an
1021:
858:
681:Rang HP, Ritter JM, Flower RJ, Henderson G (2016).
913:"Chemokine receptor oligomerization and allostery"
825:(2nd ed.). Academic Press. pp. 102–119.
750:
385:Overall signal can be increased by preventing the
1218:
2068:
1318:
968:
966:
906:
904:
816:
814:
812:
810:
808:
806:
804:
802:
800:
798:
1219:Williams DK, Wang J, Papke RL (October 2011).
910:
796:
794:
792:
790:
788:
786:
784:
782:
780:
778:
407:can be modulated in this way by adjusting the
1380:
1182:
708:
706:
704:
702:
380:
51:) is not the same one to which an endogenous
963:
901:
659:GABAA receptor negative allosteric modulator
654:GABAA receptor positive allosteric modulator
414:
1139:
1069:
1067:
1065:
1063:
775:
676:
674:
649:AMPA receptor positive allosteric modulator
102:is the ability of a substance to bind to a
1387:
1373:
1106:
854:
852:
850:
699:
228:) lower agonist affinity and/or efficacy.
1588:
1295:
1285:
1244:
1043:
998:
946:
884:
748:
685:(8th ed.). Elsevier. pp. 6–20.
332:bind between α and γ subunits of the GABA
31:are a group of substances that bind to a
1060:
671:
398:Stabilizing active/inactive conformation
351:
120:
1111:(4th ed.). Elsevier. p. 542.
847:
820:
757:(5th ed.). W.H. Freeman. pp.
347:
326:receptor positive allosteric modulators
2069:
1394:
1368:
514:
303:
55:of the receptor would bind (i.e., an
1073:
753:Lehninger Principles of Biochemistry
308:Some allosteric modulators induce a
1107:Bilezikian JP, et al. (2019).
13:
1994:Angiotensin II receptor antagonist
1938:Endocannabinoid reuptake inhibitor
1117:10.1016/B978-0-12-814841-9.00023-3
1084:10.1016/B978-0-12-411460-9.00006-9
929:10.1016/B978-0-12-394587-7.00009-9
831:10.1016/B978-0-12-803752-2.00005-3
14:
2088:
1885:Acetylcholine receptor antagonist
1647:Norepinephrine reuptake inhibitor
584:positive modulators like 4-nitro-
558:Nicotinic acetylcholine receptors
605:reducing depressive symptoms of
499:
484:
469:
454:
438:
2013:Vasopressin receptor antagonist
1927:Cannabinoid receptor antagonist
1312:
1261:
1212:
1176:
1133:
1100:
563:
423:shift to lower concentrations.
93:
1999:Endothelin receptor antagonist
1863:Acetylcholine receptor agonist
1622:Adrenergic receptor antagonist
1186:Journal of Medicinal Chemistry
1142:Journal of Medicinal Chemistry
1078:. Elsevier. pp. 187–189.
1015:
979:Journal of Medicinal Chemistry
911:Stephens B, Handel TM (2013).
877:10.1523/JNEUROSCI.2567-05.2005
742:
222:negative allosteric modulators
166:positive allosteric modulators
1:
1831:Glutamate receptor antagonist
1747:Serotonin receptor antagonist
1700:Histamine receptor antagonist
1475:Negative allosteric modulator
1469:Positive allosteric modulator
1074:Arey BJ, et al. (2014).
664:
294:
264:neutral allosteric modulators
232:is a medicine that modulates
1988:Adenosine reuptake inhibitor
1922:Cannabinoid receptor agonist
1841:Glutamate reuptake inhibitor
1760:Serotonin reuptake inhibitor
1671:Dopamine receptor antagonist
1198:10.1021/acs.jmedchem.7b01492
1154:10.1021/acs.jmedchem.8b01749
683:Rang and Dale's pharmacology
268:silent allosteric modulators
7:
1676:Dopamine reuptake inhibitor
1598:Adrenergic receptor agonist
1329:10.1016/bs.apha.2019.06.001
923:. Academic Press: 375–420.
865:The Journal of Neuroscience
637:
576:(deficits) associated with
519:
10:
2093:
1967:Opioid receptor antagonist
1821:Glutamate receptor agonist
1742:Serotonin receptor agonist
1695:Histamine receptor agonist
1109:Principles of bone biology
749:Nelson DL, Cox MM (2008).
381:Preventing desensitization
276:neutral allosteric ligands
152:
2025:
1980:
1947:
1912:
1853:
1811:
1782:
1773:
1732:
1685:
1666:Dopamine receptor agonist
1656:
1575:
1561:
1546:
1529:
1522:
1402:
1237:10.1016/j.bcp.2011.05.001
625:, which are experimental
607:major depressive disorder
592:-pyrazol-5-yl)benzamide (
415:Interaction with agonists
405:Calcium-sensing receptors
202:calcium-sensing receptors
1932:Endocannabinoid enhancer
1878:Cholinesterase inhibitor
1797:GABA receptor antagonist
1225:Biochemical Pharmacology
1972:Enkephalinase inhibitor
1962:Opioid receptor agonist
1802:GABA reuptake inhibitor
1507:♦ Miscellaneous:
1321:Neuropsychotherapeutics
1274:Neuropsychopharmacology
716:Pharmacological Reviews
328:. Benzodiazepines like
1555:Ion channel modulators
1045:10.1124/mol.117.111518
1032:Molecular Pharmacology
580:by using experimental
357:
290:, which binds to GRM5.
127:
1792:GABA receptor agonist
644:Allosteric regulation
355:
124:
29:allosteric modulators
633:positive modulators.
348:Modulating unbinding
2008:receptor antagonist
1287:10.1038/npp.2009.30
1028:Allosteric Ligands"
821:Kenakin TP (2017).
421:dose-response curve
82:means "other", and
1396:Pharmacomodulation
515:Medical importance
358:
304:Modulating binding
200:, which modulates
128:
2077:Neuropharmacology
2064:
2063:
2060:
2059:
2021:
2020:
1849:
1848:
1769:
1768:
1539:Enzyme inhibition
1148:(14): 6405–6421.
991:10.1021/jm201139r
938:978-0-12-394587-7
871:(39): 9027–9036.
840:978-0-12-803752-2
768:978-0-7167-7108-1
728:10.1124/pr.55.4.4
692:978-0-7020-5362-7
574:negative symptoms
542:neurotransmitters
288:research chemical
248:are experimental
188:, which modulate
2084:
2038:Enzyme cofactors
1957:Opioid modulator
1914:Cannabinoidergic
1780:
1779:
1586:
1585:
1573:
1572:
1527:
1526:
1389:
1382:
1375:
1366:
1365:
1359:
1358:
1316:
1310:
1309:
1299:
1289:
1280:(9): 2057–2071.
1265:
1259:
1258:
1248:
1216:
1210:
1209:
1180:
1174:
1173:
1137:
1131:
1130:
1104:
1098:
1097:
1071:
1058:
1057:
1047:
1019:
1013:
1012:
1002:
985:(4): 1445–1464.
970:
961:
960:
950:
908:
899:
898:
888:
856:
845:
844:
818:
773:
772:
756:
746:
740:
739:
710:
697:
696:
678:
588:-(1,3-diphenyl-1
503:
488:
473:
458:
442:
186:chlordiazepoxide
136:allosteric sites
132:orthosteric site
57:orthosteric site
2092:
2091:
2087:
2086:
2085:
2083:
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2081:
2067:
2066:
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2017:
2007:
1976:
1943:
1908:
1845:
1807:
1765:
1754:
1728:
1723:
1715:
1707:
1681:
1652:
1566:
1557:
1542:
1518:
1464:Inverse agonist
1454:Partial agonist
1398:
1393:
1363:
1362:
1339:
1317:
1313:
1266:
1262:
1217:
1213:
1181:
1177:
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1134:
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1105:
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1094:
1072:
1061:
1027:
1020:
1016:
971:
964:
939:
909:
902:
857:
848:
841:
819:
776:
769:
747:
743:
711:
700:
693:
679:
672:
667:
640:
630:
566:
522:
517:
510:
504:
495:
489:
480:
477:PAM-antagonists
474:
465:
459:
450:
443:
417:
400:
387:desensitization
383:
350:
335:
325:
314:benzodiazepines
306:
297:
214:PAM-antagonists
193:
174:benzodiazepines
155:
147:partial agonist
96:
49:allosteric site
37:benzodiazepines
17:
12:
11:
5:
2090:
2080:
2079:
2062:
2061:
2058:
2057:
2055:
2054:
2042:
2029:
2027:
2023:
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2019:
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2016:
2015:
2010:
2005:
2001:
1996:
1991:
1984:
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1805:
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1604:
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1570:
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1503:
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1400:
1399:
1392:
1391:
1384:
1377:
1369:
1361:
1360:
1337:
1311:
1260:
1231:(8): 915–930.
1211:
1192:(1): 159–173.
1175:
1132:
1125:
1099:
1092:
1059:
1038:(5): 504–514.
1025:
1014:
962:
937:
900:
846:
839:
774:
767:
741:
722:(4): 597–606.
698:
691:
669:
668:
666:
663:
662:
661:
656:
651:
646:
639:
636:
635:
634:
628:
603:
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521:
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468:
466:
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453:
451:
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437:
435:
416:
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399:
396:
382:
379:
363:AMPA receptors
349:
346:
333:
323:
310:conformational
305:
302:
296:
293:
292:
291:
261:
260:
259:
219:
218:
217:
211:
191:
154:
151:
95:
92:
88:conformational
43:, function as
15:
9:
6:
4:
3:
2:
2089:
2078:
2075:
2074:
2072:
2052:
2051:
2046:
2043:
2040:
2039:
2034:
2031:
2030:
2028:
2026:Miscellaneous
2024:
2014:
2011:
2009:
2002:
2000:
1997:
1995:
1992:
1989:
1986:
1985:
1983:
1979:
1973:
1970:
1968:
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1946:
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1901:
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1842:
1839:
1836:
1832:
1829:
1826:
1822:
1819:
1818:
1816:
1814:
1813:Glutamatergic
1810:
1803:
1800:
1798:
1795:
1793:
1790:
1789:
1787:
1785:
1781:
1778:
1776:
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1761:
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1724:
1718:
1716:
1710:
1708:
1701:
1698:
1696:
1693:
1692:
1690:
1688:
1687:Histaminergic
1684:
1677:
1674:
1672:
1669:
1667:
1664:
1663:
1661:
1659:
1655:
1648:
1645:
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1338:9780128166680
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1234:
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1222:
1215:
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1203:
1199:
1195:
1191:
1187:
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1147:
1143:
1136:
1128:
1126:9780128148419
1122:
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1103:
1095:
1093:9780124114609
1089:
1085:
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976:
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949:
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926:
922:
918:
914:
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828:
824:
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805:
803:
801:
799:
797:
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787:
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783:
781:
779:
770:
764:
760:
755:
754:
745:
737:
733:
729:
725:
721:
717:
709:
707:
705:
703:
694:
688:
684:
677:
675:
670:
660:
657:
655:
652:
650:
647:
645:
642:
641:
632:
624:
620:
616:
612:
611:schizophrenia
608:
604:
601:
598:
595:
591:
587:
583:
579:
578:schizophrenia
575:
572:reducing the
571:
570:
569:
561:
559:
554:
550:
547:
543:
538:
536:
531:
527:
508:
502:
497:
493:
487:
482:
478:
472:
467:
463:
457:
452:
447:
441:
436:
434:
433:concentration
430:
429:
428:
424:
422:
412:
410:
406:
395:
393:
392:Cyclothiazide
388:
378:
376:
372:
368:
365:modulated by
364:
354:
345:
343:
342:phenobarbital
339:
331:
327:
319:
315:
311:
301:
289:
285:
281:
277:
273:
269:
265:
262:
257:
254:
253:
251:
247:
243:
239:
235:
231:
227:
223:
220:
215:
212:
209:
206:
205:
203:
199:
195:
187:
183:
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175:
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167:
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162:
159:
150:
148:
143:
141:
137:
133:
123:
119:
117:
113:
109:
105:
101:
91:
89:
85:
81:
76:
74:
70:
64:
62:
58:
54:
50:
46:
42:
38:
34:
30:
26:
22:
2048:
2036:
1734:Serotonergic
1658:Dopaminergic
1537:
1320:
1314:
1277:
1273:
1263:
1228:
1224:
1214:
1189:
1185:
1178:
1145:
1141:
1135:
1108:
1102:
1075:
1035:
1031:
1017:
982:
978:
920:
916:
868:
864:
822:
752:
744:
719:
715:
682:
589:
585:
567:
564:Applications
555:
551:
539:
523:
507:NAM-agonists
506:
491:
476:
462:PAM-agonists
461:
445:
425:
418:
401:
384:
359:
338:ion channels
320:, which are
318:barbiturates
307:
298:
279:
275:
271:
267:
263:
256:NAM-agonists
255:
252:modulators.
246:dipraglurant
225:
221:
213:
208:PAM-agonists
207:
169:
165:
160:
156:
144:
140:conformation
135:
131:
129:
97:
94:Introduction
83:
79:
77:
65:
56:
48:
45:psychoactive
28:
25:biochemistry
21:pharmacology
18:
2050:Amino acids
1949:Opioidergic
1855:Cholinergic
1568:transporter
1548:Ion channel
1484:Transporter
1428:Ion channel
242:raseglurant
1898:Ganglionic
1889:Muscarinic
1867:Muscarinic
1590:Adrenergic
1459:Antagonist
665:References
367:aniracetam
295:Mechanisms
198:cinacalcet
194:-receptors
182:alprazolam
116:antagonist
2045:Precursor
1894:Nicotinic
1872:Nicotinic
1784:GABAergic
1509:Precursor
1494:Inhibitor
1420:Inhibitor
1347:1557-8925
623:LY3154207
530:evolution
526:mutations
375:glutamate
336:receptor
230:Maraviroc
2071:Category
2033:Cofactor
1903:Muscular
1563:Receptor
1514:Cofactor
1500:Releaser
1488:Enhancer
1482:♦
1445:Receptor
1443:♦
1426:♦
1409:♦
1355:31378255
1306:19295507
1255:21575610
1206:29587480
1170:73515780
1162:30817889
1054:29514854
1009:22148748
957:23415099
895:16192394
736:14657418
638:See also
631:receptor
546:overdose
535:specific
520:Benefits
330:diazepam
178:diazepam
108:Efficacy
104:receptor
100:Affinity
73:efficacy
69:affinity
33:receptor
1990:(AdoRI)
1940:(eCBRI)
1523:Classes
1449:Agonist
1437:Blocker
1415:Inducer
1297:2884290
1246:3162128
1000:3349997
948:4072031
886:6725607
449:curves.
238:Fenobam
153:Classes
112:agonist
84:stereos
61:ligands
53:agonist
41:alcohol
1934:(eCBE)
1531:Enzyme
1432:Opener
1411:Enzyme
1353:
1345:
1335:
1304:
1294:
1253:
1243:
1204:
1168:
1160:
1123:
1090:
1052:
1007:
997:
955:
945:
935:
893:
883:
837:
765:
734:
689:
582:mGluR5
196:, and
2047:(see
2035:(see
1981:Other
1804:(GRI)
1762:(SRI)
1678:(DRI)
1649:(NRI)
1565:&
1477:(NAM)
1471:(PAM)
1403:Types
1166:S2CID
594:VU-29
371:CX614
286:), a
284:5MPEP
274:) or
176:like
80:Allos
1835:NMDA
1825:AMPA
1751:5-HT
1553:See
1536:see
1502:(RA)
1496:(RI)
1490:(RE)
1351:PMID
1343:ISSN
1333:ISBN
1302:PMID
1251:PMID
1202:PMID
1158:PMID
1121:ISBN
1088:ISBN
1050:PMID
1005:PMID
953:PMID
933:ISBN
891:PMID
835:ISBN
763:ISBN
732:PMID
687:ISBN
621:and
619:DPTQ
615:DETQ
609:and
369:and
322:GABA
316:and
250:GRM5
244:and
234:CCR5
190:GABA
184:and
23:and
1325:doi
1292:PMC
1282:doi
1241:PMC
1233:doi
1194:doi
1150:doi
1113:doi
1080:doi
1040:doi
995:PMC
987:doi
943:PMC
925:doi
921:115
881:PMC
873:doi
827:doi
759:162
724:doi
492:NAM
446:PAM
280:NAL
272:SAM
226:NAM
170:PAM
39:or
19:In
2073::
2004:NK
1905:))
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1775:AA
1618:))
1577:BA
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1229:82
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1200:.
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1119:.
1086:.
1062:^
1048:.
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951:.
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903:^
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409:pH
240:,
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204:.
180:,
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63:.
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1714:2
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629:1
627:D
590:H
586:N
334:A
324:A
278:(
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192:A
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